JP4336738B2 - Pyridineaminosulfonyl substituted benzamides as inhibitors of cytochrome P4503A4 (CYP3A4) - Google Patents

Abstract

The present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, methods for their preparation, methods for their use, and pharmaceutical formulations comprising them.

Description

Therapeutic compounds S. C. In accordance with §119 (e), all of which are hereby incorporated by reference in their entirety, U.S. Patent Application No. 60 / 720,151, filed September 23, 2005, 60/723, filed October 3, 2005. No. 115, filed Oct. 11, 2005, No. 60 / 725,469, No. 60 / 762,256 filed Jan. 25, 2006, and No. 60 / 821,664 filed Aug. 7, 2006. Claim priority of issue.

  The cytochrome P450 (CYP450) enzyme system causes the biotransformation of drugs from an active form to an inactive metabolite that is easily excreted by the body. In addition, the rapid metabolism of the CYP450 enzyme system in certain drugs can significantly change their pharmacokinetic (PK) profile, and over time the plasma levels of these drugs will be sub-therapeutic. obtain. In the field of anti-infective therapy, such as treating viral infections such as human immunodeficiency virus (HIV) infection, plasma levels of such sub-therapeutic drugs can lead to increased resistance of the virus.

  Ritonavir (RTV) is a commercial HIV protease inhibitor that is also used to “boost” the pharmacokinetic exposure of many co-administered antiretroviral drugs by virtue of its ability to inhibit the cytochrome P450 3A4 enzyme Agent (PI). However, RTV is associated with clinically important gastrointestinal and metabolic side effects including nausea, vomiting, diarrhea, and dyslipidemia. Low dose administration of compounds with strong antiviral activity may also contribute to the selection of drug resistant strains of HIV. A novel CYP3A4 inhibitor that can boost antiviral drugs as effectively as RTV, but without any antiviral activity and significant side effects, will provide significant benefits and therapeutic value in the treatment of HIV-infected persons Let's go.

  The present invention discloses compounds that are useful for inhibiting the CYP450 enzyme system and can be used to boost the pharmacokinetic exposure of co-administered drugs, including antiretroviral drugs. The invention also discloses formulations comprising such compounds, methods of making them, and methods of using them.

  In one embodiment, the compound of formula (I)

（式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４は、それぞれ独立に水素、Ｃ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔハロ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＮ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＦ_３、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリールから選択され、
Ｒ^５は、水素またはＣ_１〜Ｃ_６アルキルであり、
Ｒ^６、Ｒ^７、Ｒ^８、およびＲ^９は、それぞれ独立に水素、Ｃ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔハロ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＮ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＦ_３、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＲ^１２ａ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_３〜Ｃ_１１シクロアルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＲ^１２ａ、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_３〜Ｃ_１１シクロアルキル、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、および−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）から選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_１１シクロアルキル、Ｃ_６〜Ｃ_１０アリール、Ｃ_２〜Ｃ_１０ヘテロシクリル、およびヘテロアリールはそれぞれ、１個または複数個のＲ^１４で置換されていてもよく、
Ｒ^１０およびＲ^１１は、それぞれ独立に水素、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_３〜Ｃ_１１シクロアルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリールから選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_１１シクロアルキル、Ｃ_６〜Ｃ_１０アリール、Ｃ_２〜Ｃ_１０ヘテロシクリル、およびヘテロアリール基はそれぞれ、１個または複数個のＲ^１３で置換されていてもよく、または
Ｒ^１０およびＲ^１１は、それらが結合する原子と一緒に、１個または複数個のＲ^１３で置換されていてもよいＣ_２〜Ｃ_１０ヘテロシクリル基を形成し、
各Ｒ^１２ａおよびＲ^１２ｂは、それぞれ独立に水素およびＣ_１〜Ｃ_６アルキルから選択され、または
Ｒ^１２ａおよびＲ^１２ｂは、それらが結合する原子と一緒に、Ｃ_３〜Ｃ_１１シクロアルキルまたはＣ_２〜Ｃ_１０ヘテロシクリル基を形成し、
各Ｒ^１３は、それぞれ独立にＣ_１〜Ｃ_６アルキル、ハロゲン、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＮ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＦ_３、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＣＦ_３、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_３〜Ｃ_１１シクロアルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＲ^１２ａ、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリール、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＯ_２（Ｃ_１〜Ｃ_６アルキル）、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ（Ｏ）ＮＲ^１２ａＲ^１２ｂ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＳ（Ｏ）Ｒ^１２ａ、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔＳ（Ｏ）_２Ｒ^１２ａから選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_１１シクロアルキル、Ｃ_６〜Ｃ_１０アリール、Ｃ_２〜Ｃ_１０ヘテロシクリル、およびヘテロアリール基はそれぞれ、１個または複数個のＲ^１４で置換されていてもよく、
各Ｒ^１４は、それぞれ独立にＣ_１〜Ｃ_６アルキル、ハロゲン、−ＣＮ、−ＣＦ_３、および−ＯＲ^１２ａから選択され、
各ｔは、それぞれ独立に０、１、２、３、４、５、および６から選択される）、または
その薬学的に許容できる塩もしくは溶媒和物を提供する。

(Where
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _{1 to} C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R _{^{12b) t oR 12a, - (}} CR 12a R 12b) t N (R 12a R 12b), - (CR 12a R 12b) t CF 3, and ^- (selected from _{^{CR 12a R 12b) t C 6}} ~C 10 aryl And
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OR ^12a ,-(CR ^12a R ^12b ) _t N (R ^12a R ^12b ),-(CR ^12a R ^12b ) _t R ^12a ,-(CR ^12a R ^12b) _t C ₃ ^~C _{11 ^{cycloalkyl, - (CR 12a R 12b)}} t C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, - (CR 12a R 12b)}} t heteroaryl _{^{aryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 3 ~C 11 cycloalkyl, -O (CR _{^{2a R 12b) t C 6 ~C}} 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, -O (CR 12a R 12b)}} t _{^{heteroaryl, -O (CR 12a R 12b)}} t OR ^12a, and ^{-O (CR} 12a _R ^12b) is selected from ^{t N (R 12a R 12b)} , wherein the _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 -C ₁₀ heterocyclyl and heteroaryl may each be substituted with one or more R ¹⁴ ;
R ¹⁰ and R ¹¹ are each independently hydrogen, — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C _{10 ^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 -C ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹³ , or R ¹⁰ and R ¹¹ are form but together with the atoms connecting the one or more optionally substituted with R ¹³ C ₂ ~C ₁₀ heterocyclyl group And,
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b , together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Each t is independently selected from 0, 1, 2, 3, 4, 5, and 6), or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _{1 to} C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R _{^{12b) t oR 12a, - (}} CR 12a R 12b) t N (R 12a R 12b), and ^- it is selected from _{^{(CR 12a R 12b) t CF}} 3,
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OR ^12a ,-(CR ^12a R ^12b ) _t N (R ^12a R ^12b ),-(CR ^12a R ^12b ) _t R ^12a ,-(CR ^12a R ^12b) _t C ₃ ^~C _{11 ^{cycloalkyl, - (CR 12a R 12b)}} t C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, - (CR 12a R 12b)}} t heteroaryl _{^{aryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 3 ~C 11 cycloalkyl, -O (CR _{^{2a R 12b) t C 6 ~C}} 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, -O (CR 12a R 12b)}} t _{^{heteroaryl, -O (CR 12a R 12b)}} t OR ^12a, and ^{-O (CR} 12a _R ^12b) is selected from ^{t N (R 12a R 12b)} , wherein the _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 -C ₁₀ heterocyclyl and heteroaryl may each be substituted with one or more R ¹⁴ ;
R ¹⁰ and R ¹¹ are each independently hydrogen, — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C _{10 ^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 -C Each of the ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may be substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

In yet another embodiment,
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OR ^12a ,-(CR ^12a R ^12b ) _t N (R ^12a R ^12b ),-(CR ^12a R ^12b ) _t R ^12a ,-(CR ^12a R ^12b) _t C ₃ ^~C _{11 ^{cycloalkyl, - (CR 12a R 12b)}} t C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, - (CR 12a R 12b)}} t heteroaryl _{^{aryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 3 ~C 11 cycloalkyl, -O (CR _{^{2a R 12b) t C 6 ~C}} 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, -O (CR 12a R 12b)}} t _{^{heteroaryl, -O (CR 12a R 12b)}} t OR ^12a, and ^{-O (CR} 12a _R ^12b) is selected from ^{t N (R 12a R 12b)} , wherein the _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 -C ₁₀ heterocyclyl and heteroaryl may each be substituted with one or more R ¹⁴ ;
R ¹⁰ and R ¹¹ are each independently hydrogen, — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C _{10 ^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 -C Each of the ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may be substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

In yet another embodiment,
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OR ^12a ,-(CR ^12a R ^12b ) _t N (R ^12a R ^12b ),-(CR ^12a R ^12b ) _t R ^12a ,-(CR ^12a R ^12b) _t C ₃ ^~C _{11 ^{cycloalkyl, - (CR 12a R 12b)}} t C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, - (CR 12a R 12b)}} t heteroaryl _{^{aryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 3 ~C 11 cycloalkyl, -O (CR _{^{2a R 12b) t C 6 ~C}} 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, -O (CR 12a R 12b)}} t _{^{heteroaryl, -O (CR 12a R 12b)}} t OR ^12a, and ^{-O (CR} 12a _R ^12b) is selected from ^{t N (R 12a R 12b)} , wherein the _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 -C ₁₀ heterocyclyl and heteroaryl may each be substituted with one or more R ¹⁴ ;
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, _{^{- (CR 12a R 12b) t}} C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 -C Each of the ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may be substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

The present invention further includes
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, _{^{- (CR 12a R 12b) t}} C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 -C Each of the ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may be substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

Yet another embodiment is
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, and the C ₆ -C ₁₀ aryl may be substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

Yet another embodiment is
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CR ^12a R ^12b ) C ₆ -C ₁₀ aryl or — (CR ^12a R ^12b ) ₂ C ₆ -C ₁₀ aryl, and the C ₆ -C ₁₀ aryl is one or more Optionally substituted with R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

Yet another embodiment is
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
R ^12a is hydrogen or C ₁ -C ₆ alkyl;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

Other embodiments are:
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl;
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
R ^12a is hydrogen or C ₁ -C ₆ alkyl;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

In another embodiment,
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, —Cl, —F, —CN, —CF ₃ , and —OCF ₃ Salts or solvates are provided.

In yet another embodiment,
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is C ₁ -C ₆ alkyl, —OCH ₃ , or —OCH ₂ CH ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, —Cl, —F, —CN, —CF ₃ , and —OCF ₃ Salts or solvates are provided.

In yet another embodiment,
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is —CH ₃ , —OCH ₃ , or —OCH ₂ CH ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, —Cl, —F, —CN, —CF ₃ , and —OCF ₃ Salts or solvates are provided.

In other embodiments,
R ¹ , R ² , and R ⁴ are hydrogen,
R ³ is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, —Cl, —F, —CN, —CF ₃ , and —OCF ₃ Salts or solvates are provided.

In other embodiments,
R ¹ , R ² , and R ⁴ are hydrogen,
R ³ is —CH ₃ , —OCH ₃ or —OCH ₂ CH ₃ ,
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, —Cl, —F, —CN, —CF ₃ , and —OCF ₃ Salts or solvates are provided.

In yet another embodiment,
R ¹ , R ² , and R ⁴ are hydrogen,
R ³ is —OCH ₃ or —OCH ₂ CH ₃ ,
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and the C ₆ -C ₁₀ aryl is independently selected from —Cl and —F. Provided is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with one or more of the substituents described above.

In another embodiment,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen;
R ¹⁰ is hydrogen or —CH ₃ ,
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

In another embodiment,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are hydrogen;
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

In yet another embodiment,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen;
R ¹⁰ is —CH ₃ ;
R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

further,
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OR ^12a ,-(CR ^12a R ^12b ) _t N (R ^12a R ^12b ),-(CR ^12a R ^12b ) _t R ^12a ,-(CR ^12a R ^12b) _t C ₃ ^~C _{11 ^{cycloalkyl, - (CR 12a R 12b)}} t C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, - (CR 12a R 12b)}} t heteroaryl _{^{aryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 3 ~C 11 cycloalkyl, -O (CR _{^{2a R 12b) t C 6 ~C}} 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 _{^{heterocyclyl, -O (CR 12a R 12b)}} t _{^{heteroaryl, -O (CR 12a R 12b)}} t OR ^12a, and ^{-O (CR} 12a _R ^12b) is selected from ^{t N (R 12a R 12b)} , wherein the _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 -C ₁₀ heterocyclyl and heteroaryl may each be substituted with one or more R ¹⁴ ;
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

Yet another embodiment is
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

In another embodiment,
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
R ^12a is hydrogen or C ₁ -C ₆ alkyl;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

In yet another embodiment,
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is C ₁ -C ₆ alkyl, halo, —CN, —OR ^12a , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
R ^12a is hydrogen or C ₁ -C ₆ alkyl;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF _3. Giving things.

In other embodiments,
R ¹ , R ³ , and R ⁴ are hydrogen,
R ² is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

Other embodiments are:
R ¹ , R ² , and R ⁴ are hydrogen,
R ³ is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ⁵ is hydrogen;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Give things.

In still other embodiments,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen;
R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted with one or more R ¹³ ;
A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF ₃ Offer things.

  In another embodiment, the compound of formula (I)

（式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４は、それぞれ独立に水素、Ｃ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔハロ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＮ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）から選択され、
Ｒ^５は、水素またはＣ_１〜Ｃ_６アルキルであり、
Ｒ^６、Ｒ^７、Ｒ^８、およびＲ^９は、それぞれ独立に水素、Ｃ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔハロ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣＮ、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａ、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）から選択され、
Ｒ^１０およびＲ^１１は、それぞれ独立に水素、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_１〜Ｃ_６アルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_３〜Ｃ_１１シクロアルキル、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリールから選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_１１シクロアルキル、Ｃ_６〜Ｃ_１０アリール、Ｃ_２〜Ｃ_１０ヘテロシクリル、およびヘテロアリール基はそれぞれ、少なくとも１個のＲ^１３で置換されていてもよく、または
Ｒ^１０およびＲ^１１は、それらが結合する原子と一緒に、少なくとも１個のＲ^１３で置換されていてもよいＣ_２〜Ｃ_１０ヘテロシクリル基を形成し、
各Ｒ^１２ａおよびＲ^１２ｂは、それぞれ独立に水素およびＣ_１〜Ｃ_６アルキルから選択され、または
Ｒ^１２ａおよびＲ^１２ｂは、それらが結合する原子と一緒に、Ｃ_３〜Ｃ_１１シクロアルキル基を形成し、
各Ｒ^１３は、それぞれ独立にＣ_１〜Ｃ_６アルキル、ハロゲン、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＲ^１２ａ、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_６〜Ｃ_１０アリール、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔＣ_２〜Ｃ_１０ヘテロシクリル、−Ｏ（ＣＲ^１２ａＲ^１２ｂ）_ｔヘテロアリール、−ＣＯ_２（Ｃ_１〜Ｃ_６アルキル）、−（ＣＲ^１２ａＲ^１２ｂ）_ｔＮ（Ｒ^１２ａＲ^１２ｂ）、−Ｃ（Ｏ）ＮＲ^１２ａＲ^１２ｂ、および−（ＣＲ^１２ａＲ^１２ｂ）_ｔＯＲ^１２ａから選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_６〜Ｃ_１０アリール、Ｃ_２〜Ｃ_１０ヘテロシクリル、およびヘテロアリール基はそれぞれ、少なくとも１個のＲ^１４で置換されていてもよく、
各Ｒ^１４は、それぞれ独立にＣ_１〜Ｃ_６アルキル、ハロゲン、および−ＯＲ^１２ａから選択され、
各ｔは、それぞれ独立に０、１、２、３、４、５、および６から選択される）、または
その薬学的に許容できる塩もしくは溶媒和物を提供する。

(Where
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _{1 to} C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b) _t oR ^12a, and ^- is selected from _{^{(CR 12a R 12b) t N}} (R 12a R 12b),
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t OR ^12a , ^and- (CR ^12a R ^12b ) _t N (R ^12a R ^12b ),
R ¹⁰ and R ¹¹ are each independently hydrogen, — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C _{10 ^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 -C ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with at least one R ¹³ , or R ¹⁰ and R ¹¹ are attached together with the atoms, to form at least one optionally substituted with R ¹³ C ₂ ~C ₁₀ heterocyclyl group
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached form a C ₃ -C ₁₁ cycloalkyl group And
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen, —O (CR ^12a R ^12b ) _t R ^12a , —O (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, —O (CR ^12a R ^12b) _t C ₂ ~C _{10 ^{heterocyclyl, -O (CR 12a R 12b)}} t _heteroaryl, -CO _{2 (C} 1 _{~C 6 ^{alkyl), - (CR 12a R 12b}} ) t N (R 12a R 12b) , —C (O) NR ^12a R ^12b , and — (CR ^12a R ^12b ) _t OR ^12a , wherein the C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and hetero Each aryl group may be substituted with at least one R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, and —OR ^12a ;
Each t is independently selected from 0, 1, 2, 3, 4, 5, and 6), or a pharmaceutically acceptable salt or solvate thereof.

In other embodiments,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _{1 to} C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b) _t oR ^12a, and ^- is selected from _{^{(CR 12a R 12b) t N}} (R 12a R 12b),
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently hydrogen, C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t halo, — (CR ^12a R ^12b ) _t CN, — (CR ^12a R ^12b ) _t OR ^12a , ^and- (CR ^12a R ^12b ) _t N (R ^12a R ^12b ),
R ¹⁰ and R ¹¹ are each independently hydrogen, — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C _{10 ^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 -C ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with at least one R ¹³ , or R ¹⁰ and R ¹¹ are attached together with the atoms, to form at least one optionally substituted with R ¹³ C ₂ ~C ₁₀ heterocyclyl group
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b together with the atoms to which they are attached form a C ₃ -C ₁₁ cycloalkyl group And
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen, —O (CR ^12a R ^12b ) _t R ^12a , —O (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, —O (CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl, —O (CR ^12a R ^12b ) _t heteroaryl, —CO ₂ (C ₁ -C ₆ alkyl), and — (CR ^12a R ^12b ) _t N (R ^12a R ^12b The C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with at least one R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, and —OR ^12a ;
Provided is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

In other embodiments, compounds of formula (I) are provided wherein R ¹ , R ² , R ³ , and R ⁴ are hydrogen.

In other embodiments, compounds of formula (I) are provided wherein R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen.

In other embodiments, compounds of formula (I) are provided wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen.

In other embodiments, compounds of formula (I) are provided wherein R ⁵ is hydrogen.

In other embodiments, R ¹⁰ is hydrogen and R ¹¹ is — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl, and-(CR ^12a R ^12b ) _t heteroaryl, the C ₁ -C ₆ alkyl , _C 3 _{-C 11 cycloalkyl,} C 6 _{-C 10 aryl,} C 2 _{-C 10} respectively heterocyclyl, and heteroaryl groups may be optionally substituted with at least one ^{R 13,} the compound of formula (I) I will provide a.

In other embodiments,
R ¹¹ is — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, — (CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl, _{^{- (CR 12a R 12b) t}} C 2 ~C 10 heterocyclyl, and ^{- (CR 12a R} _12b) is selected from _t heteroaryl, wherein _C 1 -C _{6 alkyl,} C 3 _{-C 11 cycloalkyl,} C 6 -C Each of the ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may be substituted with at least one R ¹³ ;
Provided are compounds of formula (I), wherein t is 1 or 2.

In another embodiment, R ¹¹ is C ₁ -C ₆ alkyl and — (CH ₂ ) C ₆ -C ₁₀ aryl, wherein said C ₁ -C ₆ and aryl groups are C ₁ -C ₆ alkyl, halogen And a compound of formula (I), optionally substituted with at least one substituent each independently selected from -OR ^12a .

In other embodiments, compounds of formula (I) are provided wherein R ¹¹ is C ₁ -C ₆ alkyl.

In other embodiments, R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group that is optionally substituted with at least one R ^13. Of the compound.

In another embodiment, the _C 2 _{-C 10} heterocyclyl _group, C 1 -C _{6 alkyl,} C 6 _{-C 10} aryl, -OH, -OCH _3, heteroaryl, and _-CO 2 _(C 1 ~C ₆ Alkyl) is optionally substituted with at least one substituent selected independently from each other, and the C ₆ -C ₁₀ aryl and heteroaryl groups are at least one halogen or a C ₁ -C ₆ alkyl group Provided is a compound of formula (I), which may be substituted.

In another embodiment, the _C 2 _{-C 10} heterocyclyl group, 2,7-diazaspiro [3.5] non-7-yl, 2,7-diazaspiro [3.5] non-2-yl, piperazinyl, Provided is a compound of formula (I) selected from piperidinyl, morpholinyl, and pyrrolidinyl.

  In other embodiments, N- [1,1-dimethyl-2- (4-methylpiperidin-1-yl) ethyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (1,1 -Dimethyl-2-piperidin-1-ylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (1,1-dimethyl-2-pyrrolidin-1-ylethyl) -2-[(pyridine- 3-ylamino) sulfonyl] benzamide; N- (1-cyclopropyl-1-methylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2-fluorobenzyl) -2-[(pyridine -3-ylamino) sulfonyl] benzamide; 2- (2,7-diazaspiro [3.5] non-7-ylcarbonyl) -N-pyridin-3-i Benzenesulfonamide; 2- (2,7-diazaspiro [3.5] non-2-ylcarbonyl) -N-pyridin-3-ylbenzenesulfonamide; N-cyclohexyl-2-[(pyridin-3-ylamino) Sulfonyl] benzamide; N- (4-fluorobenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; tert-butyl 7- {2-[(pyridin-3-ylamino) sulfonyl] benzoyl} -2, 7-diazaspiro [3.5] nonane-2-carboxylate; tert-butyl 2- {2-[(pyridin-3-ylamino) sulfonyl] benzoyl} -2,7-diazaspiro [3.5] nonane-7- Carboxylate; N-benzyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; -{[4- (4-Fluorophenyl) piperazin-1-yl] carbonyl} -N-pyridin-3-ylbenzenesulfonamide; N- (tert-butyl) -2-[(pyridin-3-ylamino) sulfonyl Benzamide; N-methyl-2- (piperidin-1-ylcarbonyl) -N-pyridin-3-ylbenzenesulfonamide; N- (5-methoxypyridin-3-yl) -2- (piperidin-1-yl) Carbonyl) benzenesulfonamide; N-butyl-2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (4-methoxypyridin-3-yl) -2- (piperidine-1- Ylcarbonyl) benzenesulfonamide; N-butyl-2-{[(4-methoxypyridin-3-yl) amino] sulfonyl N-pyridin-3-yl-2- (pyrrolidin-1-ylcarbonyl) benzenesulfonamide; 2- (morpholin-4-ylcarbonyl) -N-pyridin-3-ylbenzenesulfonamide; N- (5 -Cyanopyridin-3-yl) -2- (piperidin-1-ylcarbonyl) benzenesulfonamide; N- [1- (hydroxymethyl) cyclopentyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N -Butyl-2-{[(5-cyanopyridin-3-yl) amino] sulfonyl} benzamide; 2-[(3,5-dimethylpiperidin-1-yl) carbonyl] -N-pyridin-3-ylbenzenesulfone Amido; 2-[(4-Methoxypiperidin-1-yl) carbonyl] -N-pyridin-3-ylbe 2-{[(2R, 6S) -2,6-dimethylmorpholin-4-yl] carbonyl} -N-pyridin-3-ylbenzenesulfonamide; 2-[(4-hydroxypiperidine-1- Yl) carbonyl] -N-pyridin-3-ylbenzenesulfonamide; 2-[(3,3-dimethylpiperidin-1-yl) carbonyl] -N-pyridin-3-ylbenzenesulfonamide; N- (5- Methylpyridin-3-yl) -2- (piperidin-1-ylcarbonyl) benzenesulfonamide; N-butyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (2 -Methyl-2-morpholin-4-ylpropyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (1,1 Dimethyl-2-morpholin-4-ylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- [2- (benzyloxy) -1,1-dimethylethyl] -2-[(pyridine-3 -Ylamino) sulfonyl] benzamide; 2-[(4-methylpiperazin-1-yl) carbonyl] -N-pyridin-3-ylbenzenesulfonamide; ethyl 4- {2-[(pyridin-3-ylamino) sulfonyl] Benzoyl} piperazine-1-carboxylate; N- [2- (dimethylamino) ethyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (1,1-dimethylpropyl) -2-[( Pyridin-3-ylamino) sulfonyl] benzamide; N- (2-hydroxy-1,1-dimethylethyl)- 2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-ethyl-N- [2- (1H-pyrazol-1-yl) ethyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; 2 -[(4-methylpiperidin-1-yl) carbonyl] -N-pyridin-3-ylbenzenesulfonamide; N- (3-methylbutyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (3-Fluorobenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2,2-dimethylpropyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2 , 6-Dimethoxybenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (3-methoxy N-methyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-methyl-N-pentyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (cyclopropylmethyl) -2- [ (Pyridin-3-ylamino) sulfonyl] benzamide; N-isopropyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-propyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- ( 3,5-dimethoxybenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (1H-indol-4-ylmethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2,4-Dimethoxybenzyl) -2-[(pyridin-3-ylamino) Sulfonyl] benzamide; N- (cyclopropylmethyl) -N-propyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-benzyl-N-methyl-2-[(pyridin-3-ylamino) sulfonyl] N- (2-phenoxyethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (4-methoxybenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2,3-dihydro-1H-inden-2-yl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (3-butoxypropyl) -2-[(pyridin-3-ylamino) sulfonyl Benzamide; N- [2- (3-methoxyphenyl) ethyl] -2-[(pyridine-3-i N-pentyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-pyridin-3-yl-2-[(4-pyridin-2-ylpiperazin-1-yl) carbonyl Benzenesulfonamide; N-butyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (cyclopentylmethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-cyclobutyl-2- [(Pyridin-3-ylamino) sulfonyl] benzamide; 2-[(Pyridin-3-ylamino) sulfonyl] -N- (2-Pyridin-2-ylethyl) benzamide; 2- (Piperidin-1-ylcarbonyl) -N -Pyridin-3-ylbenzenesulfonamide; N-methyl-N- (2 Phenylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; 2-[(pyridin-3-ylamino) sulfonyl] -N- (3-pyridin-2-ylpropyl) benzamide; N- (1, 1-dimethyl-2-morpholin-4-ylethyl) -2-[(pyridin-3-ylmethyl) sulfinyl] benzamide; N- [3- (difluoromethoxy) benzyl] -2-[(pyridin-3-ylamino) sulfonyl N- (2-ethoxybenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (2-fluorobenzyl) -N-methyl-2-[(pyridin-3-ylamino) sulfonyl Benzamide; N- (2-methylbenzyl) -2-[(pyridin-3-ylamino) sulfoni N- [2- (2-methylphenyl) ethyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- [2- (3-methylphenyl) ethyl] -2-[(pyridine) -3-ylamino) sulfonyl] benzamide; N- (2-phenylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N-benzyl-N-ethyl-2-[(pyridin-3-ylamino) Sulfonyl] benzamide; N- (4-methylbenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (3-methylbenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- {4-[(methylamino) carbonyl] benzyl} -2-[(pyridin-3-ylamino) sulfonyl N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; 2- (3,4-dihydroisoquinoline-2 (1H)- Ylcarbonyl) -N-pyridin-3-ylbenzenesulfonamide; N- {4-[(dimethylamino) methyl] benzyl} -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- (3,4 -Difluorobenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- [4- (1-hydroxy-1-methylethyl) benzyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide N- (2,3-difluorobenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide 2- (1,3-dihydro-2H-isoindol-2-ylcarbonyl) -N-pyridin-3-ylbenzenesulfonamide; 2- (anilinosulfonyl) -N- (quinolin-6-ylmethyl) benzamide; 2- (anilinosulfonyl) -N- (2-methoxybenzyl) benzamide; and N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N -A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof selected from methylbenzamide.

  Another embodiment is N- (3,4-difluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2- {[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N -[4-Fluoro-3- (trifluoromethyl) benzyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-dichlorobenzyl) -2- { [(5-Methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [4-Fluoro-3- (trifluoromethyl) benzyl] -2-{[(5-methoxy Pyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-dichlorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4- Difluorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino ] Sulfonyl} -N-methylbenzamide; 2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; N- (3 , 4-Difluorobenzyl) -N-methyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3 4-difluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- (4-fluorobenzyl) -2-{[(5-methoxypyridine-3 -Yl) amino] sulfonyl} -5- (2-morpholin-4-ylethoxy) benzamide; N- (4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -5 -(Piperidin-4-yloxy) benzamide; N- (3-chloro-4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4- Difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- [4-fluoro- 3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridine -3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[ (4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; N- (4-chloro-2-methylbenzyl) -2-{[ (5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-chloro-6-fluorobenzyl) -2-{[(5-methoxypi Din-3-yl) amino] sulfonyl} benzamide; N- (2,4-difluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro- 2-methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino ] Sulfonyl} -N-methylbenzamide; N- (3-chlorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2,3-dichlorobenzyl) -2 -{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-chloro-4-fluorobenzyl) -2-{[(5 Methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [1- (4-chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3 -Chloro-2-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro-4-fluorobenzyl) -2-{[(5-methyl Pyridin-3-yl) amino] sulfonyl} benzamide; N- (3-fluoro-4-methylbenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3 5-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [1- (3,4-difluoro Rophenyl) -1-methylethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-methyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl } -N- [4- (trifluoromethyl) benzyl] benzamide; N- (3-chloro-4-methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N -(4-Chloro-3-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N- [4- (trifluoromethyl) benzyl] benzamide; and N- (4-fluorobenzyl) -5-methoxy-2-{[( - providing methoxypyridin-3-yl) amino] sulfonyl} compound selected from benzamide, or a pharmaceutically acceptable salt or solvate thereof.

  Other embodiments include N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2- {[(4-Methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- [4-Fluoro-3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3 -Yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) 2-{[(4-Ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-Ethoxypyridin-3-yl) a NO] sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; N- (4-fluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- (4-fluorobenzyl) -N-methylbenzamide; N- (2-fluorobenzyl) -2- {[(4-Methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- (2-fluorobenzyl)- N-methylbenzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N- [4- (trifluoromethyl) ) Benzyl] benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N- [4- (trifluoromethyl) benzyl] benzamide; N- (3-fluorobenzyl) 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; and 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- (3- A compound selected from (fluorobenzyl) -N-methylbenzamide or a pharmaceutically acceptable salt or solvate thereof is provided.

  Yet another embodiment is N-butyl-2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (4-methoxypyridin-3-yl) -2- (piperidine-1 -Ylcarbonyl) benzenesulfonamide; N-butyl-2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N-isopropyl-2-{[(4-methoxypyridine- 3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N-pentylbenzamide; 2-{[(4-methoxy Pyridin-3-yl) amino] sulfonyl} -N- (3-methylbutyl) benzamide; N- (1-cyclopropylethyl) -2-{[( -Methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- Butyl-2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-isopropyl-N 2-methyl [benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N-pentylbenzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- (3-methylbutyl) benzamide; N- (1-cyclopropylethyl) -2-{[(4-ethoxypyridine-3-i ) Amino] sulfonyl} benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- (3,4-difluorobenzyl ) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl } -N-methylbenzamide; N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (tert-butyl ) -2-{[(4-Methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2- {[(4-Ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- Methyl benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; N- (tert-butyl) -2- {[(4-Ethoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N- (2-phenoxyethyl) benzamide; N- ( 2-ethoxyethyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-fluoro Enyl) ethyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N- {2- [ 2- (trifluoromethoxy) phenyl] ethyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[ (4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- (2-phenoxyethyl) benzamide; N- (2-ethoxyethyl) -2-{[(4-ethoxypyridin-3-yl) amino] Sulfonyl} benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- (2-methoxyethyl) benzamide; N (2-methoxyethyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl}- N- (2-methoxyethyl) -N-methylbenzamide; N- (4-fluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2- { [(4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- (4-fluorobenzyl) -N-methylbenzamide; N-isopropyl-N- (2-methoxyethyl) -2-{[(4- Methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-isopropyl -N- (2-methoxyethyl) benzamide; N- (2-fluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4 -Ethoxypyridin-3-yl) amino] sulfonyl} -N- (2-fluorobenzyl) -N-methylbenzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl- N- [4- (trifluoromethyl) benzyl] benzamide; 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N- [4- (trifluoromethyl) benzyl] benzamide N- (sec-butyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (sec-butyl)- -{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N- (2-methylbutyl) benzamide; 2- { [(4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- (2-methylbutyl) benzamide; N-[(1R) -1,2-dimethylpropyl] -2-{[(4-methoxypyridine- 3-yl) amino] sulfonyl} benzamide; N-[(1R) -1,2-dimethylpropyl] -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N-[(1S ) -1,2-dimethylpropyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-[(1S) -1,2-di Tylpropyl] -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (1,1-dimethylpropyl) -2-{[(4-methoxypyridin-3-yl) amino] Sulfonyl} benzamide; N- (1,1-dimethylpropyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-fluorobenzyl) -2-{[(4 -Methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; and 2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N- (3-fluorobenzyl) -N-methyl Provided is a compound selected from benzamide or a pharmaceutically acceptable salt or solvate thereof.

  Yet another embodiment is 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- (3,4-difluorobenzyl ) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-butyl-2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl-N-pentylbenzamide; 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl -N- (3-methylbutyl) benzamide; N- (cyclopropylmethyl) -2-{[(5-methoxypyridin-3-yl) (methyl) amino] sulfoni } -N-propylbenzamide; N- (3,4-dichlorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [4-fluoro-3- (trifluoro) Methyl) benzyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N- (3-methylbutyl ) Benzamide; 2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- (3,4-dichlorobenzyl) -2- {[(5-Ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(5-ethoxypi Din-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2- { [(5-Ethoxypyridin-3-yl) amino] sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; N- (3,4-difluorobenzyl) -2-{[( 5-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- (4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -5- ( 2-morpholin-4-ylethoxy) benzamide; N- (4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfo Nyl} -5- (piperidin-4-yloxy) benzamide; N- (3-chloro-4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-isopropyl -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl-5- (2-morpholin-4-ylethoxy) benzamide; N-isopropyl-N- (2-methoxyethyl)- 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-isopropyl-2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methyl-5- ( Piperidin-4-yloxy) benzamide; N- [2- (2-chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-i ) Amino] sulfonyl} benzamide; N- [3- (2-methoxyphenyl) propyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (4-chloro-2- Methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-chloro-6-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl ) Amino] sulfonyl} benzamide; N- (2,4-difluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (1-isopropyl-2-methylpropyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-cyclopentylethyl) -2- [(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro-2-methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-2-adamantyl-2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (cyclohexylmethyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl } Benzamide; N- [1- (4-chlorobenzyl) -2-hydroxyethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2-fluorobenzyl)- 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- (1-ethylpropyl) ) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chlorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide N-[(1S) -2-cyclohexyl-1- (hydroxymethyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N-[(2-hydroxy-2 -Adamantyl) methyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (2,3-dichlorobenzyl) -2-{[(5-methoxypyridin-3-yl ) Amino] sulfonyl} benzamide; N- (2-chloro-4-fluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfo N} [1- (4-chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro-2-fluorobenzyl)- 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (3-chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl } Benzamide; N- [1- (3,4-difluorophenyl) -1-methylethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro- 4-methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (3,4-difluorophenyl) -1-methylethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (4-chloro-3-fluorobenzyl) -2-{[(5-methoxypyridine- 3-yl) amino] sulfonyl} benzamide; and N- (4-fluorobenzyl) -5-methoxy-2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide or a compound thereof Pharmaceutically acceptable salts or solvates are provided.

  In another embodiment, N-methyl-N- (3-methylbutyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (cyclopentylmethyl) -N-methyl-2 -{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N-methyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl} -N-pentylbenzamide; N- ( 3,4-difluorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-methylphenyl) ethyl] -2-{[(5-methyl Pyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-difluorobenzyl)- N-methyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -2-{[(5-methylpyridin-3-yl ) Amino] sulfonyl} benzamide; 2-{[(5-methylpyridin-3-yl) amino] sulfonyl} -N- {2- [2- (trifluoromethoxy) phenyl] ethyl} benzamide; N- (3- Chloro-4-fluorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3-fluoro-4-methylbenzene) Dil) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3,5-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] Sulfonyl} benzamide; N-methyl-N- [2- (2-methylphenyl) ethyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N-methyl-2-{[ (5-methylpyridin-3-yl) amino] sulfonyl} -N- [4- (trifluoromethyl) benzyl] benzamide; and N- (1-isopropyl-2-methylpropyl) -2-{[(5- A compound selected from methylpyridin-3-yl) amino] sulfonyl} benzamide or a pharmaceutically acceptable salt or solvate thereof is provided.

  In another embodiment, N-methyl-N- (2-phenylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- [2- (3-methoxyphenyl) ethyl] -2- [ (Pyridin-3-ylamino) sulfonyl] benzamide; N- (2-phenylethyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide; N- [2- (3-methylphenyl) ethyl] -2- [(Pyridin-3-ylamino) sulfonyl] benzamide; N- [2- (2-methylphenyl) ethyl] -2-[(pyridin-3-ylamino) sulfonyl] benzamide; 2-{[(5-methoxypyridine- 3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; 2-{[(5-methoxypyridine-3 Yl) amino] sulfonyl} -N-methyl-N- (2-phenylethyl) benzamide; N-methyl-2-{[(5-methylpyridin-3-yl) amino] sulfonyl} -N- (2-phenyl) Ethyl) benzamide; N- [2- (2-methylphenyl) ethyl] -2-{[methyl (pyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-methylphenyl) ethyl]- 2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) Ethyl] benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; 2- { (4-Ethoxypyridin-3-yl) amino] sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- [2- (2-methoxyphenyl) ethyl] -2-{[(5 -Methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-fluorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-Chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-fluorophenyl) ethyl] -2-{[( 5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -2-{[(5-methylpyridin-3-yl ) Amino] sulfonyl} benzamide; 2-{[(5-methylpyridin-3-yl) amino] sulfonyl} -N- {2- [2- (trifluoromethoxy) phenyl] ethyl} benzamide; N- [2- (2-Fluorophenyl) ethyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N— {2- [2- (trifluoromethoxy) phenyl] ethyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [1- (4-chlorobenzyl) -2-hydroxyethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzene N- [2- (2,5-difluorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2,4-difluorophenyl) ) Ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-methylphenyl) ethyl] -2-{[(4-methylpyridine-3- Yl) amino] sulfonyl} benzamide; N-methyl-N- [2- (2-methylphenyl) ethyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [2 -(3-Chlorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (3,4-difluorophenyl) Til] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2,3-difluoro-4-methylphenyl) ethyl] -2-{[(5- Methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (3,4-difluorophenyl) -1-methylethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl Benzamide; and N- {2- [3-fluoro-4- (trifluoromethyl) phenyl] ethyl} -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide Or a pharmaceutically acceptable salt or solvate thereof.

  Another embodiment is N- (3,4-difluorobenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-methylphenyl) ethyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} Benzamide; N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzamide; N- [4-fluoro-3- (tri Fluoromethyl) benzyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; 2-{[(5-ethoxypyridin-3-yl) amino Sulfonyl} -N- [2- (2-methylphenyl) ethyl] benzamide; N- (3,4-dichlorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; N -(3,4-difluorobenzyl) -2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; 2-{[(4-ethoxypyridin-3-yl) amino] Sulfonyl} -N- [4-fluoro-3- (trifluoromethyl) benzyl] benzamide; 2-{[(5-ethoxypyridin-3-yl) amino] sulfonyl} -N- [4-fluoro-3- ( Trifluoromethyl) benzyl] benzamide; N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfoni } -N-methylbenzamide; N- (4-chloro-2-methylbenzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3-chloro-2-methyl Benzyl) -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide; and N- (3,5-dichlorobenzyl) -2-{[(5-methylpyridin-3-yl) amino ] Sulfonyl} benzamide; N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide or a pharmaceutically acceptable compound thereof Provided salts or solvates that can be produced.

  In another embodiment, N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide; N- (3,4-difluorobenzyl ) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- [2- (2-fluorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) Amino] sulfonyl} benzamide; N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide; N- (3,4- Difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; and N- (3,4-difluorobenzyl) -2- Providing [(4-ethoxy-3-yl) amino] sulfonyl} -N- methyl compound selected from benzamide, or a pharmaceutically acceptable salt or solvate thereof.

  In another embodiment, N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide, or a pharmaceutically acceptable salt or A solvate is provided. Another embodiment provides N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide, or a pharmaceutically acceptable salt or solvate thereof. provide. Another embodiment is N- [2- (2-fluorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide, or a pharmaceutically acceptable salt or solvent thereof Offer Japanese products. Another embodiment is N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide, or a pharmaceutically acceptable salt thereof Salts or solvates are provided. Another embodiment provides N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide, or a pharmaceutically acceptable salt or solvate thereof. provide. Another embodiment is N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide, or a pharmaceutically acceptable salt or A solvate is provided.

  In other embodiments, pharmaceutical compositions comprising an effective amount of at least one compound of formula (I) and a pharmaceutically acceptable carrier are provided. In another embodiment, a pharmaceutical composition is provided that further comprises an effective amount of at least one compound that is metabolized by the cytochrome P450 3A4 enzyme. In another embodiment, the pharmaceutical composition is provided wherein the at least one compound that is metabolized by the cytochrome P450 3A4 enzyme is an anti-HIV compound.

  The present invention is further a pharmaceutical composition comprising an effective amount of at least one compound metabolized by the cytochrome P450 enzyme and an effective amount of any compound of formula (I). In another embodiment, the pharmaceutical composition is provided wherein the at least one anti-HIV compound is an HIV protease inhibitor. In another embodiment, the HIV protease inhibitor is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, invilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX- 478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[( -Hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and phosamprenavir calcium provide. In another embodiment, the HIV protease inhibitor is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brecanavir, brecanavir, (4R) -N-allyl- 3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4- There is provided such a pharmaceutical composition selected from carboxamide and phosamprenavir calcium. In another embodiment, the at least one other compound is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino. ] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide.

  Another embodiment is an effective amount of (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3 -Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine- Ethyl 5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] Pyridin-1-yl) -8-azabiciq [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide), at least one compound of formula (I), and a pharmaceutically acceptable carrier. I will provide a. The present invention further provides an effective amount of (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3. 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), at least a compound of formula (I), and a pharmaceutically acceptable carrier. .

  Another embodiment is the combination of at least one compound of formula (I) and anti-HIV as a combined formulation for simultaneous, separate or sequential administration to an HIV-infected mammal for the treatment of HIV in said mammal A pharmaceutical composition comprising the compound is provided.

  In another embodiment, by a cytochrome P450 3A4 enzyme, comprising administering to the mammal a first compound and an effective amount of a second compound, wherein the second compound is selected from those of formula (I) Methods of inhibiting metabolism of a first compound that is metabolized are provided. The present invention further provides that the first compound is 6-cyclopentyl-6- [2- (2,6-diethylpyridin-4-yl) ethyl] -3-[(5,7-dimethyl [1,2,4]. ] Such a method, which is triazolo [1,5-a] pyrimidin-2-yl) methyl] -4-hydroxy-5,6-dihydro-2H-pyran-2-one, or a pharmaceutically acceptable salt thereof. provide. In another embodiment, the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-. Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3 -(3-Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] Ethyl pyridine-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5 -C] pyridin-1-yl) -8 Azabicyclo [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such a method. The present invention further provides that the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo. [3.2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide). In another embodiment, such a method is provided wherein said first compound is an anti-HIV compound. In other embodiments, such methods are provided wherein the anti-HIV compound is an HIV protease inhibitor. In another embodiment, the HIV protease inhibitor is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-me Rubenzoiru) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, provides such a method. In another embodiment, the HIV protease inhibitor is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3 -{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide And phosamprenavir calcium is provided. In another embodiment, the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-. Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide) is provided.

  In another embodiment of the first compound comprising administering to the mammal a first compound and an effective amount of the second compound, wherein the second compound is selected from those of formula (I) Methods are provided for improving pharmacokinetics in mammals. In another embodiment, the first compound is 6-cyclopentyl-6- [2- (2,6-diethylpyridin-4-yl) ethyl] -3-[(5,7-dimethyl [1,2, 4] Such a method, which is triazolo [1,5-a] pyrimidin-2-yl) methyl] -4-hydroxy-5,6-dihydro-2H-pyran-2-one, or a pharmaceutically acceptable salt thereof. I will provide a. The present invention further provides that the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo. [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3-Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] Ethyl pyridine-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5- c] Pyridin-1-yl) -8- Zabishikuro [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such a method. In another embodiment, the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8- Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide) is provided. In another embodiment, such a method is provided wherein said first compound is an anti-HIV compound. In other embodiments, such methods are provided wherein the anti-HIV compound is an HIV protease inhibitor. In another embodiment, the HIV protease inhibitor is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-me Rubenzoiru) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, provides such a method. In another embodiment, the HIV protease inhibitor is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3 -{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide And phosamprenavir calcium is provided. In yet another embodiment, the HIV protease inhibitor is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino]-. 4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide is provided.

  Another embodiment comprises administering to an HIV infected mammal an effective amount of a first compound and an effective amount of a second compound, wherein the first compound is an HIV replication inhibitor compound, Provided is a method of inhibiting HIV replication in said mammal, wherein the compound is selected from those of formula (I). In yet another embodiment, the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8. -Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino)- 3- (3-Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5- c] ethyl pyridine-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4 5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-yl] is 1- (3-fluorophenyl) propyl} acetamide), it provides such a method. In yet another embodiment, the first compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8. -Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide). Yet another embodiment provides such a method, wherein the anti-HIV compound is an HIV protease inhibitor. In another embodiment, the HIV protease inhibitor is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-methyl Benzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, provides such a method. In yet another embodiment, the HIV protease inhibitor is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl- 3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4- There is provided such a method selected from carboxamide and phosamprenavir calcium. In another embodiment, the first compound is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4 -Phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide is provided.

  The invention further provides a first in the preparation of a medicament for treating HIV infection in an HIV-infected mammal, wherein the first compound is selected from those of formula (I) and the second compound is an anti-HIV compound. And the use of a second compound. The present invention further provides that the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo. [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3-Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] Ethyl pyridine-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5- c] Pyridin-1-yl) -8- Zabishikuro [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such use. In another embodiment, the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8- Azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide). Yet another embodiment provides such use, wherein the second compound is an HIV protease inhibitor. In another embodiment, the second compound is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, invilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-methylbenzoyl Amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, resulting in such use. In another embodiment, the second compound is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3 -{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide , And fosamprenavir calcium are provided. In another embodiment, the second compound is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4 -Phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide is provided for such use. Other embodiments provide such use wherein the medicament is for simultaneous, separate or sequential administration to the mammal for the treatment of HIV.

  A first compound in the preparation of a medicament for improving the pharmacokinetics of a second compound in a mammal, wherein the first compound is selected from those of formula (I) and the second compound is metabolized by cytochrome P450. Use of the compound and the second compound. Further, the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3. 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3- Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5 -Ethyl carboxylate or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine -1-yl) -8-azabi B [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such use. Further, the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3. 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide). Further provided is such use, wherein said second compound is an HIV protease inhibitor. In another embodiment, the second compound is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, invilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-methylbenzoyl Amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, resulting in such use. The present invention further provides that the second compound is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3- {(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, And such use selected from phosamprenavir calcium. In another embodiment, the second compound is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4 -Phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide is provided for such use.

  The invention further provides for improving the pharmacokinetics of a second compound in a mammal wherein the first compound is selected from those based on formula (I) and the second compound is metabolized by cytochrome P450. Includes the first compound in the preparation of a medicament. Further, the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3. 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3- Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5 -Ethyl carboxylate or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine -1-yl) -8-azabi B [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such use. Further, the second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3. 2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide). Further provided is such use, wherein said second compound is an HIV protease inhibitor. In another embodiment, the second compound is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, invilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-methylbenzoyl Amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, resulting in such use. The present invention further provides that the second compound is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3- {(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, And such use selected from phosamprenavir calcium. In another embodiment, the second compound is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4 -Phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide is provided for such use.

  In other embodiments, any of the methods described herein are provided wherein the administration of the first and second compounds occurs sequentially.

  In other embodiments, any of the methods described herein are provided wherein the administration of the first and second compounds occurs simultaneously.

  In another embodiment, there is provided a method of treating HIV in a mammal comprising administering to the HIV infected mammal an effective amount of an anti-HIV compound and an effective amount of a compound based on formula (I). In other embodiments, such methods are provided wherein the anti-HIV compound is an HIV protease inhibitor. In another embodiment, the HIV protease inhibitor is amprenavir, CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, TMC-126, atazanavir, parinavir, GS-3333. , KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX -478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy- 2-me Rubenzoiru) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and are selected from fosamprenavir calcium, provides such a method. In another embodiment, the HIV protease inhibitor is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, brenavir, (4R) -N-allyl-3 -{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide And phosamprenavir calcium. In other embodiments, the HIV protease inhibitor is (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4- Such a process is provided which is phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide. In another embodiment, the anti-HIV compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [ 3.2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- ( 3-Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine Ethyl-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] Pyridin-1-yl) -8- Zabishikuro [3.2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), provides such a method. In another embodiment, the anti-HIV compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [ 3.2.1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide).

  In other embodiments, the first compound is 6-cyclopentyl-6- [2- (2,6-diethylpyridin-4-yl) ethyl] -3-[(5,7-dimethyl [1,2,4]. ] Such a method is provided which is triazolo [1,5-a] pyrimidin-2-yl) methyl] -4-hydroxy-5,6-dihydro-2H-pyran-2-one.

  As used herein, the terms “comprising” and “including” are used in their non-exclusive and non-limiting sense.

  As used herein, the term “HIV” refers to human immunodeficiency virus. The term “HIV integrase” refers herein to the human immunodeficiency virus integrase enzyme.

The term “C ₁ -C ₆ alkyl” refers herein to a saturated monovalent hydrocarbon group having a linear or branched moiety and containing 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

The term “C ₃ -C ₁₁ cycloalkyl” represents a saturated, monocyclic, fused, or spiro, polycyclic ring structure having a total of 3 to 11 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.

The term “C ₆ -C ₁₀ aryl” refers herein to a group derived from an aromatic hydrocarbon containing 6 to 10 carbon atoms. Examples of such groups include but are not limited to phenyl or naphthyl. The terms “Ph” and “phenyl” as used herein represent a —C ₆ H ₅ group. The term “benzyl” refers herein to the group —CH ₂ C ₆ H ₅ .

The term “C ₂ -C ₁₀ heterocyclyl” as used herein has a total of 4 to 10 atoms in the ring system and is independent of 2 to 10 carbon atoms and O, S and N, respectively. Represents a non-aromatic, monocyclic, bicyclic, tricyclic or tetracyclic group containing 1 to 4 heteroatoms selected from: wherein the ring of the group comprises two Does not contain adjacent O atoms or two adjacent S atoms. Furthermore, such _C 2 _{-C 10} heterocyclyl group, polycyclic and may contain a spiro ring systems. Such a group may be benzo-fused. Moreover, according C ₂ -C ₁₀ heterocyclyl group may be any available atom that will result in stable compounds contain an oxo substituent. For example, such groups may contain oxo atoms with available carbon or nitrogen atoms. Such groups may contain two or more oxo substituents where chemically possible. Furthermore, if such C ₂ -C ₁₀ heterocyclyl group contains a sulfur atom, said sulfur atom may be understood that is oxidized with one or two oxygen atoms, can result in sulfoxide or sulfone I want. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Other examples of such C ₂ -C ₁₀ heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl , Azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, Dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinini , Imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, there are 3H- indolyl and quinolizinyl, it just is not limited.

  The term “heteroaryl” as used herein has a total of 5 to 10 atoms in the ring and is independently selected from 2 to 9 carbon atoms and O, S and N, respectively. Represents an aromatic heterocyclic group containing ˜4 heteroatoms, provided that the ring of said group does not contain 2 adjacent O atoms or 2 adjacent S atoms. Heterocyclic groups include benzofused ring systems. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinfurinyl, cinfurinyl Indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and phlopyridinyl. Where such is possible, the heteroaryl group may be C-bonded or N-bonded. By way of example, a group derived from pyrrole may be pyrrol-1-yl (N-bond) or pyrrol-3-yl (C-bond). Further, the group derived from imidazole may be imidazol-1-yl (N bond) or imidazol-3-yl (C bond).

  The terms “halogen” and “halo” as used herein represent fluorine, chlorine, bromine or iodine.

The term “substituted” indicates that the specified group or moiety bears one or more substituents. The term “unsubstituted” indicates that the specified group has no substituent. The term “optionally substituted” indicates that the specified group is unsubstituted or substituted by one or more substituents. In the compounds of the present invention, when a group is said to be “unsubstituted” or “substituted” with less than the number at which all atoms in the compound are satisfied, such a group It should be understood that the remaining valence of is filled with hydrogen. For example, if a C ₆ aryl group, also referred to herein as “phenyl”, is substituted with one other substituent, such a group will have an open position on the carbon atom of the C ₆ aryl ring ( one skilled in the art understands that four open positions) remain (from six initial positions, one subtracts the position to which the remainder of the compound of the invention is attached, subtracts another substituent) and four remain. Let's be done. In such a case, the remaining four carbon atoms are each bonded to one hydrogen atom to satisfy their valence. Similarly, if the C ₆ aryl group in this compound is said to be “disubstituted”, those skilled in the art will understand that C ₆ aryl represents the remaining three carbon atoms remaining. Like. Those three unsubstituted carbon atoms are each bonded to one hydrogen atom to fill their valence.

  The term “solvate” as used herein refers to a pharmaceutically acceptable solvate form of such a compound that retains the biological effectiveness of the compound of the invention. Examples of solvates include, but are not limited to, compounds of the present invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated by the present invention that one solvent molecule may be bound to one molecule of the compound of the invention, such as a hydrate. Furthermore, it is specifically contemplated by the present invention that two or more solvent molecules may be bound to a single molecule of the compound, such as a dihydrate. Moreover, it is specifically contemplated that less than one solvent molecule may be bound to one molecule of the compound of the invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of the compounds of the present invention that retain the biological effectiveness of the non-hydrated form of the compound.

  The term “pharmaceutically acceptable salt” as used herein retains the biological effectiveness of the free acid and free base of the specified derivative and may not be biologically or otherwise undesirable. Represents no salt of the compound of the invention.

  The terms “cytochrome P450 inhibitory amount” and “cytochrome P450 enzyme activity inhibitory amount” are used herein to reduce the activity of a cytochrome P450 enzyme or the activity of a particular cytochrome P450 enzyme isoform in the presence of a compound. Means the amount of such compound. Whether a particular compound reduces cytochrome P450 enzyme activity, and the amount of such compound required to do so, is determined by methods known to those of skill in the art and as described herein. be able to.

  The terms “inhibit” or “inhibition” are used herein to refer to cytochrome P450 enzymes using agents that can reduce the activity described below in vitro or in vivo after administration to a mammal such as a human. It means to reduce the activity (s). Such inhibition can be effected by the direct binding of the compound to cytochrome P450 enzyme (s). Moreover, if such direct binding between the enzyme and the compound is not performed, the activity of such cytochrome P450 enzymes can be reduced in the presence of such compounds. In addition, T.W. F. Woolf, Handbook of Drug Metabolism, Marcel Dekker, Inc. , New York, 1999, such inhibition may be competitive, non-competitive, or uncompetitive. Such inhibition can be determined using methods known to those skilled in the art, using in vitro or in vivo systems, or a combination of both.

As used herein, the term “bioavailability” refers to the systemic availability of a given amount of a compound administered to a mammal. Bioavailability can be assessed by measuring the area under the curve (AUC) or maximum serum or plasma concentration (C _max ) of the unmodified form of the compound after administration of the compound to the mammal. AUC is the determination of the area under the curve that plots the serum or plasma concentration of a compound along the vertical axis (Y axis) against time along the horizontal axis (X axis). In general, the AUC for a particular compound is determined using methods known to those skilled in the art and G.P. S. Banker, Modern Pharmaceuticals, Drugs and the Pharmaceutical Sciences, v. 72, Marcel Dekker, New York, Inc. , 1996, can be calculated. The C _max value is defined as the maximum concentration of compound achieved in the mammal's serum or plasma after administration of the compound to the mammal. The C _max value of a particular compound can be measured using methods known to those skilled in the art. The expression “increased bioavailability” or “improved pharmacokinetics” is used herein to refer to the systemic availability of the first compound measured as AUC, C _max , or C _{min in} a mammal. This shows that the combined administration with the compound of the present invention is larger than the case where such combined administration is not performed.

  The terms “administration”, “administering”, “dosage” and “dosing” are used herein to mean that a compound is absorbed into the serum or plasma of a mammal. Delivery of a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the compound, or a pharmaceutically acceptable salt or solvate thereof, to such a mammal.

  The terms “administration in combination” or “administering in combination” as used herein mean administration of a combination of a first compound and a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof. Such concomitant administration can be performed such that the first compound and the compound of the invention are part of the same composition or part of the same unit dosage form. Co-administration includes administering the first compound and the compound of the invention separately but as part of the same treatment regime. When administered separately, the two components need not be administered essentially simultaneously, but may be so desired. Thus, co-administration includes, for example, administering the first compound and the compound of the invention as separate dosages or dosage forms, but simultaneously. Combination administration also includes individual administration at different times and in any order.

  The term “pharmaceutically acceptable formulation” or “pharmaceutical composition” as used herein is compatible with a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as well as a compound of the invention, Represents a combination of carriers, diluents, and / or excipients that are not harmful to the recipient. The formulation can be prepared by procedures known to those skilled in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers suitable for such formulations include the following: fillers and bulking agents such as starches, sugars, mannitol, and silicic acid derivatives; binders such as carboxymethylcellulose and Other cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone; humectants such as glycerine; disintegrants such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents that delay dissolution, For example, paraffins; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonite; and lubricants such as talc, stearic acid Siumu and magnesium stearate and solid polyethylene glycols. The final dosage form may be a pill, tablet, powder, lozenge, sachet, cachet, or sterile packaged powder, depending on the type of excipient used. Moreover, it is specifically contemplated that the pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the invention. Alternatively, such formulations may contain one or more compounds of the invention and one or more other anti-HIV agents.

  The term “inhibiting HIV replication” refers to inhibiting human immunodeficiency virus (HIV) replication in cells. Such cells can exist in vitro or in vivo, eg, in a mammal such as a human. Such inhibition can be achieved by administering one or more anti-HIV compounds, for example, to cells in a mammal in an HIV inhibitory amount. For example, quantification of inhibition of HIV replication in cells in mammals can be measured using methods known to those skilled in the art. For example, the anti-HIV compound can be administered to a mammal alone or as part of a pharmaceutically acceptable formulation. A blood sample can then be collected from the mammal and the amount of HIV virus in the sample can be quantified using methods known to those skilled in the art. A reduction in the amount of HIV virus in the sample compared to the amount contained in the blood prior to administration of one or more anti-HIV compounds should correspond to inhibition of replication of HIV virus in the mammal. . For example, administration of one or more anti-HIV compounds to cells in a mammal may be in a single dose or a series of dose forms. In the case of two or more administrations, the administration may be performed in one day or over two or more days.

  The terms “anti-HIV compound” and “HIV inhibitory agent” as used herein refer to a compound or combination of compounds capable of inhibiting the replication of HIV in a cell, eg, a cell in a mammal. Such compounds can inhibit HIV replication through any mechanism known to those of skill in the art.

  The terms “human immunodeficiency virus inhibitory amount”, “HIV inhibitory amount” and “HIV replication inhibitory amount” are used herein in vivo, for example in mammals, or in vitro, human immunodeficiency virus (HIV). Means the amount of an anti-HIV compound, or a pharmaceutically acceptable salt or solvate thereof, required to inhibit the replication of The amount of such compound required to cause such inhibition can be determined without undue experimentation using the methods described herein and those known to those skilled in the art.

  The term “therapeutically effective amount” or “effective amount” as used herein refers to a compound that is sufficient to effect treatment when administered to a mammal in need of such treatment, as defined herein. Represents an amount. Thus, a therapeutically effective amount or effective amount of a compound is such that the activity of such enzyme target or biological process is such that the pathology mediated by the activity of the particular enzyme target or biological process is reduced or alleviated. An amount sufficient to modulate or inhibit. Examples of modulation or inhibition of specific target enzyme targets or biological processes include, but are not limited to, inhibition of HIV protease enzymes and inhibition of CYP450 enzymes, such as CYP3A4 enzymes.

  The terms “treat”, “treating”, and “treatment” mean any treatment of any disease or condition in mammals, particularly humans, and (i) Preventing a disease or condition from occurring in a subject susceptible to that condition, such that the treatment is a prophylactic treatment of the pathological condition; (ii) modulating or inhibiting the disease or condition, ie, Stopping progression; (iii) alleviating the disease or condition, ie, causing regression of the disease or condition; or (iv) alleviating and / or alleviating symptoms resulting from the disease or condition or disease or condition. This includes, for example, alleviating the inflammatory response without addressing the underlying disease or condition.

  The terms “resistant”, “resistant”, and “resistant HIV” as used herein refer to HIV viruses that exhibit reduced sensitivity to certain drugs. Mammals infected with HIV that are resistant to certain anti-HIV agents or drug combinations usually manifest an increase in HIV viral load despite continuous administration of the drug (s). Resistance was discovered by the successful growth of a laboratory culture of HIV virus in the presence of an anti-HIV agent or a combination of such agents, or a genotype that represents a mutation in the HIV gene structure May be any of the phenotypes representing

  The terms “protease inhibitor” and “HIV protease inhibitor” are used herein to interfere with proper functioning of the HIV protease enzyme that causes cleavage of long viral proteins into the separate proteins that make up the viral core. Or a combination of compounds.

  The terms “viral load” and “HIV viral load” as used herein refer to the amount of HIV in the circulating blood of a mammal, eg, a human. The amount of HIV virus in mammalian blood can be determined by measuring the amount of HIV RNA in the blood using methods known to those skilled in the art.

  The term “compound of the invention” means any compound of formula (I), including those described in the examples below, including those described generically or as types. The term also refers to pharmaceutically acceptable salts or solvates of these compounds.

  A compound of the invention can be used in combination with another compound to increase exposure, increase the bioavailability of another compound, or improve the pharmacokinetics of another compound in a mammal. It can be administered to animals, such as humans. The term “exposure” as used herein means the concentration of another or second compound in the plasma of a mammal measured over a period of time. Increasing the exposure of a mammal to another or second compound can be accomplished by first administering another or second compound to the mammal in a suitable form and without administration of a compound of the invention, And can be measured by measuring the amount of the compound in the plasma using a suitable analytical technique such as liquid chromatography or liquid chromatography-tandem mass spectrometry. The same test is then repeated except that the compound of the invention is co-administered with another or second compound. The amount of another or second compound present in the plasma at a certain time is determined and the concentration and time data of all samples are plotted to obtain a curve. The area under the curve is calculated to give mammalian exposure to the compound. The difference in area under the curve in the presence and absence of a compound of the present invention provides a measure of increased exposure to another or second compound in mammalian plasma. The terms “exposure”, “area under the curve”, and “area under the concentration / time curve” have the same meaning and are used interchangeably throughout.

  As noted above, such combined administration of a compound of the present invention and a second or another compound to a mammal results in the compound (s) of the present invention being in the same formulation as the other drug described above. Can happen as. Alternatively, such combinations can be administered such that the compound (s) of the invention are present in a different formulation than the formulation containing another agent. When the compound (s) of the invention are administered separately from another agent, such administration can be performed simultaneously or sequentially with an appropriate period in between. The choice of whether to include the compound (s) of the present invention in the same formulation as another drug (s) is within the knowledge of one of ordinary skill in the art.

  According to conventions used in the art, symbols

は、コアまたは骨格構造への部分（ｍｏｉｅｔｙ）または置換基の結合点である結合を示すために本明細書において構造式で使用している。別の慣習によれば、本明細書においていくつかの構造式では、炭素原子およびそれらに結合した水素原子は、はっきりと示されておらず、例えば、

Is used herein in structural formulas to denote a bond that is the point of attachment of a moiety or substituent to the core or backbone structure. According to another convention, in some structural formulas herein, carbon atoms and hydrogen atoms attached to them are not clearly shown, for example,

は、メチル基を表し、

Represents a methyl group,

は、エチル基を表し、

Represents an ethyl group,

は、シクロペンチル基を表す、などである。

Represents a cyclopentyl group, and the like.

  The term “stereoisomer” means compounds that have the same chemical structure but differ in the arrangement of their atoms or groups in space. In particular, the term “enantiomer” refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term “racemic” or “racemic mixture” as used herein means a 1: 1 mixture of specific compound enantiomers. In contrast, the term “diastereoisomer” means a relationship between a pair of stereoisomers that contain two or more asymmetric centers and are not mirror images of one another.

  The compound of the present invention may have an asymmetric carbon atom. The binding of the compounds of the present invention is herein indicated by the solid line.

、塗りつぶした楔（ｓｏｌｉｄ ｗｅｄｇｅ）

, Solid wedge

、または点状の楔（ｄｏｔｔｅｄ ｗｅｄｇｅ）

Or a dotted wedge

を用いて示すことができる。不斉炭素原子からの結合を示すための実線の使用は、その炭素原子において可能な立体異性体の全てが含まれていることを示唆することを意味する。不斉炭素原子からの結合を示すための塗りつぶした楔または点状の楔のいずれかの使用は、示した立体異性体だけが含まれていなければならないことを示唆することを意味する。本発明の化合物が２個以上の不斉炭素原子を含有し得ることが可能である。それらの化合物では、不斉炭素原子からの結合を示すための実線の使用は、可能な立体異性体の全てが含まれていなければならないことを示唆することを意味する。本発明の化合物中の１個または複数個の不斉炭素原子からの結合を示すための実線の使用および同じ化合物中の他の不斉炭素原子からの結合を示す塗りつぶした楔または点状の楔の使用は、ジアステレオ異性体の混合物が存在することを示唆することを意味する。

Can be used to indicate. The use of a solid line to indicate a bond from an asymmetric carbon atom is meant to suggest that all possible stereoisomers at that carbon atom are included. The use of either a solid wedge or a point wedge to indicate a bond from an asymmetric carbon atom is meant to suggest that only the indicated stereoisomer must be included. It is possible that the compounds of the present invention may contain 2 or more asymmetric carbon atoms. In those compounds, the use of a solid line to indicate a bond from an asymmetric carbon atom is meant to suggest that all possible stereoisomers must be included. Use of solid lines to indicate bonds from one or more asymmetric carbon atoms in the compounds of the present invention and solid or dotted wedges indicating bonds from other asymmetric carbon atoms in the same compound The use of is meant to indicate that a mixture of diastereoisomers is present.

  When the derivative used in the method of the present invention is a base, the desired salt is an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid, or an organic acid, such as acetic acid; maleic acid; Fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidic acid such as glucuronic acid or galacturonic acid; α-hydroxy acid such as citric acid or tartaric acid; Prepared by any suitable method known in the art, including treatment of the free base with a family acid such as benzoic acid or cinnamic acid; sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid Can do.

  When the derivative used in the process of the present invention is an acid, the desired salt is an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide Can be prepared by any suitable method known in the art, including treatment of the free acid with the. Examples of suitable salts include amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; cyclic amines such as piperidine, morpholine, and piperazine; and sodium, calcium, potassium, magnesium There are organic salts derived from inorganic salts derived from manganese, iron, copper, zinc, aluminum, and lithium.

  “Solvate” is intended to represent a pharmaceutically acceptable solvate form of such a compound that retains the biological effectiveness of the specified compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof There is, but is not limited to that.

  “Pharmaceutically acceptable salts” retain the biological effectiveness of the free acids and free bases of the specified derivatives containing pharmacologically acceptable anions and are biologically or otherwise. It represents a salt that is not undesirable. Examples of pharmaceutically acceptable salts include acetate, acrylate, benzenesulfonate, benzoate (eg, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate). Benzoate), bicarbonate, bisulfate, bisulfite, hydrogen tartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, cansylate, carbonate, chloride, capron Acid salt, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edslyate, estrate, esylate, ethyl succinate, formate, Fumarate, glucoceptate, gluconate, glutamate, glycolate, glycolylarsanylate plate), heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactic acid Salt, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methyl sulfate, monohydrogen phosphate, mucate ), Napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate , Phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, poly Galacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, basic acetate, suberate, succinate, sulfate, sulfonic acid Examples include, but are not limited to, salts, sulfites, tannates, tartrate, theocrate, tosylate, triethiodo, and valerate.

  Essentially basic compounds of the invention are capable of forming a wide variety of different salts with various inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but in practice, the compounds of the invention were first isolated from the reaction mixture as pharmaceutically unacceptable salts and then used with alkaline reagents. It is often desirable to simply convert the latter to the original free base compound by treatment followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention are prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. Can do. After evaporating the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base dissolved in an organic solvent by adding the appropriate mineral or organic acid to the solution.

  Essentially acidic compounds of the present invention are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, especially sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical base used as a reagent for preparing the pharmaceutically acceptable base salt of the present invention forms a non-toxic base salt with the acidic compound of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. These salts may be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution preferably to dryness under reduced pressure. it can. Alternatively, they can also be prepared by mixing together a lower alkanol solution of an acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as before. In either case, it is preferred to use stoichiometric amounts of reagents to ensure complete reaction and maximum yield of the desired end product.

  When the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be obtained by any suitable method available in the art, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphorus Acids or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid such as glucuronic acid or galacturonic acid, α-hydroxy acid Prepared by treatment of the free base with, for example, citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. it can.

  When the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be obtained by any suitable method such as an inorganic or organic base, such as an amine (primary, secondary, or tertiary), alkaline It can be prepared by treatment of a free acid using a metal hydroxide or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines and organic salts derived from cyclic amines such as piperidine, morpholine and piperazine and sodium , Inorganic salts derived from calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

  It will be appreciated by those skilled in the art that, in the case of solid drugs, the compounds, drugs and salts of the present invention can exist in different crystalline or polymorphic forms, all within the scope of the present invention and the specified formula.

  The compounds of the present invention can be formulated into pharmaceutical compositions as described below in any dosage form recognized by those skilled in the art as appropriate. The pharmaceutical composition of the invention comprises a therapeutically effective amount of at least one compound of the invention and an inert pharmaceutically acceptable carrier or diluent.

  The pharmaceutical carrier used may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the compositions of the present invention can be prepared using ethyl cellulose in combination with a time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. , Hydroxypropyl methylcellulose, methyl methacrylate, and the like. Other additives or excipients can be added to obtain the desired formulation characteristics. For example, bioavailability promoters such as Labrasol®, Gelucire®, etc., or formulators such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol) Can be added. For example, when preparing a capsule formulation, Gelucire®, a semi-solid vehicle that protects the active ingredient from light, moisture and oxidation, can be added.

  If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier can vary, but will generally be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injection or suspension in an ampoule or vial, or a non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The compositions of the invention are prepared in dosage unit forms suitable for administration methods such as parenteral or oral administration.

  To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of a compound of the invention can be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. . If a soluble salt form is not available, the drug can be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc. in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, the compound of formula I is dissolved in DMSO and diluted with water. The composition may be in the form of a solution in the form of a salt of the active ingredient dissolved in a suitable aqueous vehicle such as water or isotonic saline or dextrose solution.

  Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the compounds of the invention can be preferably formulated in aqueous solutions in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

  For oral administration, the compounds can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. With such a carrier, the compound of the present invention can be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc., for oral intake by the subject to be treated. become. Pharmaceutical preparations for oral use can be obtained by mixing solid excipients with active ingredients (drugs), optionally crushing the resulting mixture and adding appropriate auxiliaries as needed After addition, the granule mixture is processed to obtain a tablet or dragee core. Suitable excipients include fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, There are hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

  Dragee cores are provided with suitable coatings. For this, it is possible to use gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or concentrated sugar liquor which may contain titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. it can. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

  Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. Push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration must be in dosages suitable for such administration. For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner.

  For intranasal administration or administration by inhalation, the compounds for use according to the present invention may be suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. And can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to deliver a fixed amount. Capsules and cartridges made of gelatin for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

  The compounds may be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage forms, such as ampoules or multi-dose containers, with an added preservative. The composition may take the form of a suspension, solution or emulsion dissolved in an oily or aqueous vehicle and may contain preparations such as suspending, stabilizing and / or dispersing agents. .

  Formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

  Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

  Apart from the above preparation, the compound of the present invention may be formulated as a depot. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound is formulated with a suitable polymer or hydrophobic substance (eg, as an acceptable emulsion in oil) or ion exchange resin, or as a slightly less soluble derivative, eg, a slightly less soluble salt. can do.

  A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3 w / v% benzyl alcohol, 8 w / v% nonpolar surfactant polysorbate 80, and 65 w / v% polyethylene glycol 300 made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with an aqueous solution of 5% dextrose. This co-solvent system dissolves hydrophobic compounds well and itself produces low toxicity after systemic administration. The ratio of the co-solvent system can be varied appropriately without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent component can be varied. For example, other low toxicity nonpolar surfactants may be used in place of polysorbate 80; the proportion of polyethylene glycol may be varied; other biocompatible polymers such as polyvinylpyrrolidone replace polyethylene glycol. Well; and dextrose is replaced by other sugars or polysaccharides.

  Alternatively, other delivery systems for hydrophobic drug compounds may be used. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Several organic solvents such as dimethyl sulfoxide can also be used, but usually at the expense of greater toxicity due to the toxic nature of DMSO. In addition, the compounds can be delivered using a sustained release system, such as a semi-permeable substrate of a solid hydrophobic polymer containing a therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained release capsules can release compounds from weeks up to over 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, alternative strategies for protein stabilization may be used.

  The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. These carriers and excipients can provide a significant improvement in the bioavailability of low solubility drugs. Examples of such carriers or excipients include polymers such as calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives, gelatin, and polyethylene glycol. In addition, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plrol®, Peceol® ) Transcutol (registered trademark) or the like can be used. Furthermore, the pharmaceutical composition can be incorporated into a skin patch to deliver the drug directly onto the skin.

  It will be appreciated that the actual dosage of the agents of the invention will vary depending on the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host and disease being treated. Like. One skilled in the art using conventional dosage determination tests in view of experimental data for a given compound can determine the optimal dosage for a given set of conditions. For oral administration, examples of commonly used daily doses will be about 0.001 to about 1000 mg / kg body weight with repeated courses of treatment at appropriate intervals.

  Further, the pharmaceutically acceptable formulation of the present invention comprises about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg of the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. Or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg.

  Moreover, a pharmaceutically acceptable formulation of the present invention comprises about 0.5 w / w% to about 95 w / w%, or about 1 w / w of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. w% to about 95 w / w%, or about 1 w / w% to about 75 w / w%, or about 5 w / w% to about 75 w / w%, or about 10 w / w% to about 75 w / w%, or about It may be contained in an amount of 10 w / w% to about 50 w / w%.

  To treat or prevent a disease or condition mediated by HIV, the pharmaceutical composition of the invention in a suitable formulation is administered in combination with at least one anti-HIV agent. A combination of a compound of the present invention and at least an anti-HIV agent comprises a therapeutically effective amount (ie cytochrome P450 inhibitory amount) of at least one compound of the present invention (as an active ingredient), one or more anti-HIV agents. And, for example, can be prepared by combining the active compound with at least one pharmaceutically suitable carrier which can be selected from diluents, excipients and auxiliaries which facilitate the processing of the active compound into a final drug preparation. .

  Alternatively, to treat or prevent a disease or condition mediated by HIV, the pharmaceutical composition of the invention in a suitable formulation is combined with at least one anti-HIV agent in another pharmaceutically acceptable formulation. Administer at the same time. Such a regimen can be designed to administer a compound of the invention to an HIV-infected mammal before, simultaneously with, or after administration of a formulation containing at least one anti-HIV agent. Pharmaceutically acceptable formulations of the compounds of the invention comprise at least one pharmaceutical agent that can be selected from the compounds and, for example, diluents, excipients, and auxiliaries that facilitate processing of the active compound into a final pharmaceutical preparation. Can be prepared by combining with a suitable carrier.

  A compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered to a mammal suffering from HIV infection, such as a human, alone or as part of a pharmaceutically acceptable formulation per day. It can be administered once, twice a day, or three times a day in combination with an anti-HIV agent.

  With respect to the compounds of the present invention, the specific formulation, dosage, and number of administrations per day to the mammal in need of such treatment, and the selection of the specific anti-HIV agent (s) are all determined by those skilled in the art. Those skilled in the art should understand that this is a choice within the knowledge and can be determined without undue experimentation. For example, as of April 16, 2004, http: // www. aidsfo. nih. See “Guidelines for the Use of Antiviral Agents in HIV-1 Infected Ads and Adolescents,” available at gov / guidelines /.

  The compounds of the invention are intended to treat mammals, such as humans, suffering from HIV virus infection, AIDS, AIDS-related complex syndrome (ARC), or any other disease or condition associated with HIV virus infection. In combination with another drug (s). Agents that can be used in conjunction with the compounds of the present invention include HIV protease inhibitors, HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, CCR5 inhibitors, HIV, as described below. There are compounds that are useful as fusion inhibitors, compounds that are useful as immunomodulators, compounds that inhibit HIV viruses by unknown mechanisms, compounds that are useful in the treatment of herpes viruses, and compounds that are useful as anti-infective agents. It is not limited.

  Compounds useful as HIV protease inhibitors that can be used in conjunction with compounds of the present invention include 141 W94 (amprenavir), CGP-73547, CGP-61755, DMP-450, nelfinavir, ritonavir, saquinavir (invilase), lopinavir , TMC-126, Atazanavir, Parinavir, GS-3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP -450, AG-1776, MK-944, VX-478, indinavir, tipranavir, darunavir, brecanavir, DPC-681, DPC-684, phosamprenavir calcium (Lexiva) ), Benzenesulfonamide derivatives disclosed in WO03053435, R-944, Ro-03-34649, VX-385, GS-224338, OPT-TL3, PL-100, SM-309515, AG-148, DG-35 -VIII, DMP-850, GW-5950X, KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003, Vb-19038, A-77003, BMS -182193, BMS-186318, SM-309515, JE-2147, GS-9005, and (4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2 -Methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl There is Le-1,3-thiazolidine-4-carboxamide, but is not limited only thereto.

  Compounds useful as inhibitors of HIV reverse transcriptase that can be used in conjunction with the compounds of the present invention include abacavir, FTC, GS-840, lamivudine, adefovir dipivoxil, β-fluoro-ddA, zalcitabine, didanosine, stavudine, zidovudine Tenofovir, Amdoxovir, SPD-754, SPD-756, Rashi Beer, Lever Set (DPC-817), MIV-210 (FLG), β-L-Fd4C (ACH-126443), MIV-310 (Alovudine, FLT), These include, but are not limited to, dOTC, DAPD, entecavir, GS-7340, emtricitabine, and alobudine.

  Compounds useful as non-nucleoside inhibitors of HIV reverse transcriptase that can be used in conjunction with compounds of the present invention include efavirenz, HBY-097, nevirapine, TMC-120 (dapivirin), TMC-125, etaravirin, delavirdine, DPC- 083, DPC-961, TMC-120, Capabililine, GW-678248, GW-695634, calanolide, and the tricyclic pyrimidinone derivatives disclosed in WO 0302238, but are not so limited.

  Compounds useful as CCR5 inhibitors that can be used in conjunction with compounds of the present invention include TAK-779, SC-351125, SCH-D, (N-{(1S) -3- [3-isopropyl-5-methyl- 4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3.2.1] oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1 -Endo- {8-[(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl- 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carboxylate, N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl) -4,5 6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} Acetamide), PRO-140, and GW-873140 (Ono-4128, AK-602), but are not limited thereto.

  Compounds useful as inhibitors of the HIV integrase enzyme that can be used in conjunction with the compounds of the present invention include GW-810781, 1,5-naphthyridine-3-carboxamide derivatives disclosed in WO 03062204, disclosed in WO 03047564 Compounds, compounds disclosed in WO 03049690, and 5-hydroxypyrimidine-4-carboxamide derivatives disclosed in WO 03035076, but are not limited thereto.

  Fusion inhibitors for treating HIV that can be used in conjunction with compounds of the present invention include fused tricyclics disclosed in Enfuvirtide (T-20), T-1249, AMD-3100, and JP 2003171381. There are, but are not limited to, compounds.

  Other compounds that are useful inhibitors of HIV that can be used in conjunction with compounds of the present invention include soluble CD4, TNX-355, PRO-542, BMS-806, tenofovir disoproxil fumarate, and disclosed in JP 200319137 But not limited thereto.

  Compounds useful for the treatment or management of infectious diseases caused by viruses other than HIV that can be used in conjunction with the compounds of the present invention include acyclovir, fomivirsen, penciclovir, HPMPC, oxetanocin G, AL-721, cidofovir, cytomegalovirus immunoglobin, Cytben, fomivganciclovir, famciclovir, foscarnet sodium, Isis 2922, KNI-272, valacyclovir, virazole ribavirin, valganciclovir, ME-609, PCL-016 .

  Compounds that act as immunomodulators and can be used in conjunction with the compounds of the present invention include AD-439, AD-519, alpha interferon, AS-101, bropirimine, acemannan, CL246, 738, EL10, FP-21399 Γ interferon, granulocyte macrophage colony stimulating factor, IL-2, intravenous immunoglobulin injection, IMREG-1, IMREG-2, diethyldithiocarbamate imthiol, α-2 interferon, methionine-enkephalin, MTP-PE, granulocyte colony stimulation Factor, remunes, rCD4, recombinant soluble human CD4, interferon alpha-2, SK & F106528, soluble T4 hymopentin, tumor necrosis factor (TNF), tucaresol, recombinant human interface Ron beta, and there are interferon .alpha.n-3, it only is not limited.

  Anti-infectives that can be used in conjunction with the compounds of the present invention include atovacon, azithromycin, clarithromycin, trimethoprim, trovafloxacin, pyrimethamine, daunorubicin, clindamycin plus primaquine, fluconazole, pastille, ornidyl , Eflornithine Pentamidine, Rifabutin, Spiramycin, Intraconazole-R5211, Trimetrexate, Daunorubicin, Recombinant Human Erythropoietin, Recombinant Human Growth Hormone, Megestrol Acetate, Testerone, and Whole Enteral Nutrition It is not limited.

  Antifungal agents that can be used in conjunction with the compounds of the present invention include, but are not limited to, anidurafungin, C31G, caspofungin, DB-289, fluconazole, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole.

  Other compounds that can be used in conjunction with the compounds of the present invention include acmannan, ansamycin, LM 427, AR177, BMS-232623, BMS-234475, CI-1012, curdlan sulfate, dextran sulfate, STOCRINE EL10, Examples include, but are not limited to, hypericin, lobukavir, novapren, peptide T octapeptide sequence, trisodium phosphonoformate, probucol, and RBC-CD4.

  Moreover, the compounds of the present invention can be used in conjunction with antiproliferative agents to treat conditions such as Kaposi's sarcoma. Such agents include inhibitors of metallomatrix proteases, A-007, bevacizumab, BMS-275291, halofuginone, interleukin-12, rituximab, paclitaxel, porfimer sodium, rebimasstat, and COL-3, It is not limited to that.

  The particular choice of another agent (s) is, but is not limited to, the condition of the mammal to be treated, the particular condition (s) to be treated, the compound (1) of the invention Species) and the identity of another agent (s), as well as the identity of any other compound used to treat the mammal. . The particular selection of the compound (s) of the invention and the other agent (s) is within the knowledge of one of ordinary skill in the art and can be made without undue experimentation.

  The compounds of the invention are intended to treat mammals, such as humans, suffering from HIV virus infection, AIDS, AIDS-related complex syndrome (ARC), or any other disease or condition associated with HIV virus infection. Can be administered in conjunction with any of the other agents described above. Such combinations can be administered to a mammal such that the compound (s) of the invention are present in the same formulation as the other agent described above. Alternatively, such a combination is afflicted with an HIV virus infection such that the compound (s) of the invention are present in a different formulation than the formulation containing the other agent. It can be administered to a mammal. When a compound of the compound (s) of the invention is administered separately from another agent, such administration can be performed sequentially, with an appropriate period of time simultaneously or in between. The choice of whether to include the compound (s) of the present invention in the same formulation as another agent (s) is within the knowledge of one of ordinary skill in the art.

  The agents of the present invention can be prepared using the reaction routes and synthetic schemes described below using techniques available in the art using readily available starting materials. The preparation of some embodiments of the present invention is described in detail in the following examples, but the described methods of preparation may be readily adapted to prepare other embodiments of the present invention. Those skilled in the art should understand. For example, the synthesis of compounds not exemplified in accordance with the present invention can be accomplished by, for example, replacing interfering groups by changing to other suitable reagents known in the art or by making routine changes in reaction conditions. It is possible to carry out with modifications that will be apparent to those skilled in the art. Alternatively, it should be appreciated that other reactions disclosed herein or known in the art have the flexibility to prepare other compounds of the invention.

Compounds of formula (I) can be prepared from compounds of formulas 3 and 4 as shown in Scheme 1 below. Generally, its R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are as defined above and R ¹⁵ is C ₁ -C ₁₀ alkyl. A compound of formula 3 can be reacted with a compound of formula 4 whose R ¹⁰ and R ¹¹ are as defined above. Such a reaction can be carried out in an aprotic solvent such as acetonitrile, for example at a temperature in the range of about 50 ° C. to about 150 ° C., for example about 110 ° C., and optionally in the presence of microwave energy. For example, a compound of formula (I) can be prepared by reacting methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate (1 equivalent) in CH ₃ CN (0.35 M) with the appropriate compound of formula 4 (1 .5 equivalents) and the resulting mixture was prepared with methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate by heating in the microwave to about 110 ° C. for 30 minutes can do. The reaction mixture is then allowed to cool to approximately room temperature and the solvent is removed by evaporation. The resulting crude product can be further purified by methods known to those skilled in the art, for example by use of silica gel chromatography with a suitable solvent or mixture of solvents as eluent.

The compound of formula 3 is as shown in Scheme 2 below, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are as defined above. And can be prepared from compounds of formulas 1 and 2 wherein R ¹⁵ is C ₁ -C ₁₀ alkyl. In general, these reactions can be carried out at a temperature in the range of about 0 ° C. to about 75 ° C., for example about 25 ° C., and in the presence of a base in an aprotic solvent such as acetonitrile. Suitable bases include, but are not limited to, inorganic bases such as potassium carbonate or sodium carbonate, or organic bases such as triethylamine or N, N-4,4-dimethylaminopyridine. Alternatively, a second equivalent of the compound of formula 2 can be used as a suitable base. The choice of whether to use another base or another equivalent of compound 2 can be determined without undue experimentation, as the base is within the knowledge of one of ordinary skill in the art.

  Compounds of formula 1 are either commercially available or found in the literature, such as Kim et al., Synthesis (1992), (12), 1203-4; Bastide et al., Pesticide Science (1994), 40 (4), 293 -7; and those found in Diehr et al., US Pat. No. 4,743,294, can be prepared by one of ordinary skill in the art without undue experimentation.

  Compounds of formula 2 are commercially available and can be prepared by one of ordinary skill in the art without undue experimentation using methods found in the literature or can be prepared using the methods described herein. .

  Inhibition of the cytochrome P450 enzyme system by the compounds of the present invention can be determined based on methods known to those skilled in the art and methods described in the specification. For example, Morrison, J. et al. F. Biochim Biophys Acta. 1969, 185: 269-86; and Szelasekek, S .; E. Ostafe, V .; Serban, M .; , And Vlad, M. et al. O. Biochem. J. et al. 1988, 254: 311-312.

  The following examples are merely illustrative of specific embodiments of the invention and are not intended to limit the scope of the invention in any way.

  In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius (° C.), and all parts and percentages are by weight unless otherwise indicated.

  Various starting materials and other reagents are available from Aldrich Chemical Company or Lancaster Synthesis Ltd. And purchased without further purification unless otherwise indicated.

  The reactions described below were performed in anhydrous solvents at ambient temperature (unless otherwise specified) under positive pressure of nitrogen, argon or using a drying tube. Analytical thin layer chromatography was performed on glass-backed silica gel 60 ° F. 254 plates (Analtech (0.25 mm)) and eluted with the appropriate solvent ratio (v / v). The reaction was assayed by high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) and stopped as judged by starting material consumption. TLC plates were visualized by UV, phosphomolybdic acid staining, or iodine staining.

Unless otherwise indicated, ¹ H-NMR spectra were recorded on a Bruker instrument operated at 300 MHz, and ¹³ C-NMR spectra were recorded at 75 MHz. NMR spectra were obtained as DMSO-d6 or CDCl ₃ solutions (reported in ppm) using chloroform (7.25 ppm and 77.00 ppm) or DMSO-d6 (2.50 ppm and 39.52 ppm) as the target standard. Other NMR solvents were used as needed. When reporting peak multiplicity, the following abbreviations are used: s = single line, d = double line, t = triple line, m = multiple line, br = broad line, dd = double duplex Line, dt = double triple line. If the binding constant is indicated, report it in hertz.

Infrared spectra are recorded on a Perkin-Elmer FT-IR spectrometer as neat oil, KBr pellets, or CDCl ₃ solution and reported at wavenumber (cm ⁻¹ ). Mass spectra were obtained using LC / MS or APCI. All melting points have not been corrected.

  The purity of all final products (by HPLC at 220 nm and 254 nm wavelengths) was higher than 95%.

  All elemental analyzes of compounds herein yield C, H, and N analysis values that were within 0.4% of the theoretical values, unless otherwise specified, and are reported as “C, H, N” To do.

In the examples and preparations below, “LDA” represents lithium diisopropylamide, “Et” represents ethyl, “Ac” represents acetyl, “Me” represents methyl, and “Ph” represents , Phenyl, (PhO) ₂ POCl represents chlorodiphenyl phosphate, “HCl” represents hydrochloric acid, “EtOAc” represents ethyl acetate, “Na ₂ CO ₃ ” represents sodium carbonate , “NaOH” represents sodium hydroxide, “NaCl” represents sodium chloride, “NEt ₃ ” represents triethylamine, “THF” represents tetrahydrofuran, and “DIC” represents diisopropylcarbodiimide. "HOBt" represents a hydroxy benzotriazole, _{"H 2} O" refers to water, "NaHCO _3" is bicarbonate Na Represents potassium, _"K 2 CO _3" represents potassium carbonate, "MeOH" stands for methanol, "i-PrOAc" represents isopropyl acetate, "MgSO _4" represents a magnesium sulfate, " “DMSO” represents dimethyl sulfoxide, “AcCl” represents acetyl chloride, “CH ₂ Cl ₂ ” represents methylene chloride, “MTBE” represents methyl t-butyl ether, “DMF” represents dimethyl sulfoxide. Represents formamide, “SOCl ₂ ” represents thionyl chloride, “H ₃ PO ₄ ” represents phosphoric acid, “CH ₃ SO ₃ H” represents methanesulfonic acid, and “Ac ₂ O” represents Represents acetic anhydride, “CH ₃ CN” represents acetonitrile, and “KOH” represents potassium hydroxide.

(Example A)
2-[(Pyridin-3-ylamino) sulfonyl] benzoic acid methyl ester

２−（クロロスルホニル）安息香酸メチル（１４．１ｇ、６０．０ｍｍｏｌ）を、撹拌した３−ピリジンアミン（１５．０ｇ、１５９．４ｍｍｏｌ）のＣＨ_３ＣＮ（０．４Ｍ）溶液に加えた。温度は、２５℃まで上昇し、少量の赤味を帯びた油が分離した。ＣＨＣｌ_３（２．０Ｍ、アミレンで保護された）を加えて、全ての物質を溶液に戻した。１時間後、溶媒を蒸発させ、残留油をＥｔＯＡｃと水の間で分配した。有機層を水で洗浄し、蒸発させて、粗製生成物を得た。粗製生成物を最少量の熱ＥｔＯＡｃ中に溶解させ、エーテルで希釈した。生成物は、急速に結晶化させ、１時間後にろ過して取り出し、エーテルで洗浄して、表題化合物を生成した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ８．３８（ｄ，１Ｈ）８．３１（ｄ，２Ｈ）７．９３（ｄ，２Ｈ）７．８０（ｄ，２Ｈ）７．７６（ｔ，１Ｈ）７．６４（ｔ，１Ｈ）７．５３（ｔ，１Ｈ）７．２５（ｍ，１Ｈ）４．１２（ｓ，３Ｈ）。

Methyl 2- (chlorosulfonyl) benzoate (14.1 g, 60.0 mmol) was added to a stirred solution of _3- pyridinamine (15.0 g, 159.4 mmol) in CH ₃ CN (0.4M). The temperature rose to 25 ° C and a small amount of reddish oil separated. CHCl ₃ (2.0 M, amylene protected) was added to bring all material back into solution. After 1 hour, the solvent was evaporated and the residual oil was partitioned between EtOAc and water. The organic layer was washed with water and evaporated to give the crude product. The crude product was dissolved in a minimum amount of hot EtOAc and diluted with ether. The product crystallized rapidly and was filtered off after 1 hour and washed with ether to yield the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, 1H) 8.31 (d, 2H) 7.93 (d, 2H) 7.80 (d, 2H) 7.76 (t, 1H) 7 .64 (t, 1H) 7.53 (t, 1H) 7.25 (m, 1H) 4.12 (s, 3H).

A mixture of methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate (1 eq) and the appropriate amine (1.5 eq) dissolved in CH ₃ CN (0.35 M) was prepared and microwaved. The compound of formula (I) was prepared using methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate by heating in to about 110 ° C. for 30 minutes. The solution was allowed to cool to room temperature and the solvent was evaporated. The crude product was purified by SiO ₂ column chromatography.

(Example B)
2-{[(5-Methylpyridin-3-yl) amino] sulfonyl} methyl benzoate

５−メチルピリジン−３−アミン（０．５ｇ、４．６２ｍｍｏｌ）のＣＨ_２Ｃｌ_２（５０ｍｌ）溶液に、トリエチルアミン（０．６４ｍＬ、４．６２ｍｍｏｌ）および２−（クロロスルホニル）安息香酸メチル（１．０８ｇ、４．６２ｍｍｏｌ）を加えた。得られた混合物を室温で１時間撹拌した。次いで混合物を飽和ＮａＨＣＯ_３水溶液で希釈し、ＣＨ_２Ｃｌ_２で抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過および濃縮した。粗製の残留物をフラッシュクロマトグラフィー（０〜８％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）によって精製して、表題化合物（０．４７６ｇ、３４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ ｐｐｍ １０．２５〜１０．６２（ｍ，１Ｈ）８．６（ｓ，２Ｈ）７．８１〜７．９３（ｍ，１Ｈ）７．６４〜７．７６（ｍ，２Ｈ）７．５４〜７．６４（ｍ，１Ｈ）７．２８（ｓ，１Ｈ）３．８０（ｓ，３Ｈ）２．１８（ｓ，３Ｈ）。

To a solution of 5-methylpyridin-3-amine (0.5 g, 4.62 mmol) in CH ₂ Cl ₂ (50 ml) was added triethylamine (0.64 mL, 4.62 mmol) and methyl 2- (chlorosulfonyl) benzoate (1 0.08 g, 4.62 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.476 g, 34%). ¹ H NMR (400 MHz, DMSO-D6) δ ppm 10.25 to 10.62 (m, 1H) 8.6 (s, 2H) 7.81 to 7.93 (m, 1H) 7.64 to 7. 76 (m, 2H) 7.54 to 7.64 (m, 1H) 7.28 (s, 1H) 3.80 (s, 3H) 2.18 (s, 3H).

Mixture of methyl 2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzoate (1 eq) and the appropriate amine (1.5 eq) dissolved in CH ₃ CN (0.35 M) And heating the compound of formula (I) with methyl 2-{[(5-methylpyridin-3-yl) amino] sulfonyl} benzoate by heating to about 110 ° C. in a microwave for 30 minutes. Prepared. The solution was allowed to cool to room temperature and the solvent was evaporated. The crude product was purified by SiO ₂ column chromatography.

(Example C)
Preparation of methyl 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzoate Step 1: 3-Bromo-5-methoxypyridine

蒸留ヘッドを備えたフラスコに入れた３，５−ジブロモピリジン（１０．０ｇ、４２．２ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に、２５％ｗｔ／ｗｔ ＮａＯＭｅ溶液（１０ｍＬ）を加え、混合物を１００℃まで３時間加熱した。３時間経った後、ＭｅＯＨ約８ｍＬを捕集した。ＤＭＦ溶液を室温まで冷却し、Ｈ_２Ｏ（２５ｍＬ）で希釈し、ＭＴＢＥ（２×２５ｍＬ）で抽出した。混合有機層をＨ_２Ｏ（２×２５ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、ろ過および濃縮した。次いで残留物を高真空下で１０時間乾燥させて、表題化合物（５．２ｇ、６６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ８．２６〜８．３１（ｍ，２Ｈ）７．６９〜７．７２（ｍ，１Ｈ）３．８４（ｓ，３Ｈ）。

To a solution of 3,5-dibromopyridine (10.0 g, 42.2 mmol) in DMF (10 mL) in a flask equipped with a distillation head is added 25% wt / wt NaOMe solution (10 mL) and the mixture is brought to 100 ° C. Heated for 3 hours. After 3 hours, about 8 mL of MeOH was collected. The DMF solution was cooled to room temperature, diluted with H ₂ O (25 mL) and extracted with MTBE (2 × 25 mL). The combined organic layer was washed with H ₂ O (2 × 25 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was then dried under high vacuum for 10 hours to give the title compound (5.2 g, 66%). ¹ H NMR (400 MHz, DMSO-D6) δ 8.26-8.31 (m, 2H) 7.69-7.72 (m, 1H) 3.84 (s, 3H).

  Step 2: 5-methoxypyridin-3-amine

３−ブロモ−５−メトキシピリジン（５．２ｇ、２７．５ｍｍｏｌ）とＣｕＳＯ_４・Ｈ２Ｏ（１．３７ｇ、５．５ｍｍｏｌ）のＮＨ_４ＯＨ（５ｍＬ）溶液を封管中に入れ、１２０℃で１０時間加熱した。次いで反応混合物を室温まで冷却し、Ｈ_２Ｏ（４０ｍＬ）で希釈し、ＥｔＯＡｃ（３×３０ｍＬ）で抽出した。混合有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過および濃縮して、表題化合物をもたらし、それをさらに精製しないで次のステップで使用した。

A solution of 3-bromo-5-methoxypyridine (5.2 g, 27.5 mmol) and CuSO ₄ .H 2 O (1.37 g, 5.5 mmol) in NH ₄ OH (5 mL) was placed in a sealed tube, and 10 Heated for hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (40 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound that was used in the next step without further purification.

  Step 3: 2-{[(5-Methoxypyridin-3-yl) amino] sulfonyl} methyl benzoate

５−メトキシピリジン−３−アミン（１等量）のピリジン（０．４Ｍ）溶液に、２−（クロロスルホニル）安息香酸メチル（１等量）を加え、混合物を室温で終夜撹拌した。混合物を飽和ＮａＨＣＯ_３水溶液で希釈し、ＣＨ_２Ｃｌ_２で抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過および濃縮した。粗製の残留物をフラッシュクロマトグラフィー（０〜８％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）によって精製し、表題化合物を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ ｐｐｍ １０．５６〜１０．６６（ｍ，１Ｈ）８．５５〜８．６１（ｍ，１Ｈ）７．９５〜８．０１（ｍ，１Ｈ）７．８６〜７．９４（ｍ，１Ｈ）７．６７〜７．７３（ｍ，２Ｈ）７．３４〜７．４０（ｍ，１Ｈ）７．０２（ｓ，１Ｈ）３．８３（ｓ，３Ｈ）３．７３（ｓ，３Ｈ）。

To a solution of 5-methoxypyridin-3-amine (1 equivalent) in pyridine (0.4 M) was added methyl 2- (chlorosulfonyl) benzoate (1 equivalent) and the mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH / CH ₂ Cl ₂ ) to give the title compound. ¹ H NMR (400 MHz, DMSO-D6) δ ppm 10.56 to 10.66 (m, 1H) 8.55 to 8.61 (m, 1H) 7.95 to 8.01 (m, 1H) 86-7.94 (m, 1H) 7.67-7.73 (m, 2H) 7.34-7.40 (m, 1H) 7.02 (s, 1H) 3.83 (s, 3H) 3.73 (s, 3H).

Mixture of methyl 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzoate (1 eq) and the appropriate amine (1.5 eq) dissolved in CH ₃ CN (0.35 M) And the compound of formula (I) with methyl 2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzoate is heated in a microwave for 30 minutes to about 110 ° C. Prepared. The solution was allowed to cool to room temperature and the solvent was evaporated. The crude product was purified by SiO ₂ column chromatography.

(Example D)
Preparation of methyl 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzoate Step 1: 4-methoxypyridin-3-amine

４−メトキシ−３−ニトロピリジン（２．５ｇ、１６．２ｍｍｏｌ）のＭｅＯＨ（５０ｍＬ）溶液に、１０％ｗｔ／ｗｔ Ｐｄ／Ｃ（０．５ｇ）を加え、混合物を１ａｔｍ Ｈ_２下、室温で１０時間撹拌した。反応混合物をセライトに通してろ過し、ろ液を濃縮した。粗製の残留物をフラッシュクロマトグラフィー（０〜１０％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）によって精製して、化合物１６（０．８７５ｇ、４４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ７．８３（ｓ，１Ｈ）７．７０（ｄ，１Ｈ）６．７９（ｄ，１Ｈ）４．７９（ｓ，２Ｈ）３．７９（ｓ，３Ｈ）。

4-methoxy-3-nitropyridine (2.5 g, 16.2 mmol) in MeOH (50 mL) solution of, 10% wt / wt Pd / C a (0.5 g) was added, the mixture 1 atm H ₂ under room temperature Stir for 10 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude residue was purified by flash chromatography (0-10% MeOH / CH ₂ Cl ₂ ) to give compound 16 (0.875 g, 44%). ¹ H NMR (400 MHz, DMSO-D6) δ 7.83 (s, 1H) 7.70 (d, 1H) 6.79 (d, 1H) 4.79 (s, 2H) 3.79 (s, 3H) .

  Step 2: 2-{[(4-Methoxypyridin-3-yl) amino] sulfonyl} methyl benzoate

５−メトキシピリジン−３−アミン（１等量）のピリジン（０．４Ｍ）溶液に、２−（クロロスルホニル）安息香酸メチル（１等量）を加え、混合物を室温で終夜撹拌した。混合物を飽和ＮａＨＣＯ_３水溶液で希釈し、ＣＨ_２Ｃｌ_２で抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過および濃縮した。粗製の残留物をフラッシュクロマトグラフィーによって精製して、表題化合物を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ９．３５〜９．５７（ｍ，１Ｈ）８．５４〜８．６１（ｍ，１Ｈ）８．１７〜８．２３（ｍ，１Ｈ）７．７４〜７．８５（ｍ，２Ｈ）７．６１〜７．７３（ｍ，１Ｈ）７．３２〜７．４２（ｍ，１Ｈ）６．９１〜７．００（ｍ，１Ｈ）３．７３（ｓ，３Ｈ）３．５１（ｓ，３Ｈ）

To a solution of 5-methoxypyridin-3-amine (1 equivalent) in pyridine (0.4 M) was added methyl 2- (chlorosulfonyl) benzoate (1 equivalent) and the mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography to give the title compound. ¹ H NMR (400 MHz, DMSO-D6) δ 9.35 to 9.57 (m, 1H) 8.54 to 8.61 (m, 1H) 8.17 to 8.23 (m, 1H) 7.74 to 7.85 (m, 2H) 7.61 to 7.73 (m, 1H) 7.32 to 7.42 (m, 1H) 6.91 to 7.00 (m, 1H) 3.73 (s, 3H) 3.51 (s, 3H)

Mixture of methyl 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzoate (1 eq) and the appropriate amine (1.5 eq) dissolved in CH ₃ CN (0.35 M) And the compound of formula (I) using methyl 2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzoate by heating to about 110 ° C. in a microwave for 30 minutes. Prepared. The solution was allowed to cool to room temperature and the solvent was evaporated. The crude product was purified by SiO ₂ column chromatography.

(Example E)
Preparation of methyl 2-{[(5-cyanopyridin-3-yl) amino] sulfonyl} benzoate Scharina, T .; Et al. Methyl 2-{[(5-cyanopyridin-3-yl) amino] sulfonyl} benzoate was prepared according to the procedure published in Organometallic Chemistry 2004, 689, 4576.

ＣＨ_３ＣＮ（０．３５Ｍ）に溶かした２−｛［（５−シアノピリジン−３−イル）アミノ］スルホニル｝安息香酸メチル（１等量）と適切なアミン（１．５等量）の混合物を調製し、マイクロ波中で約１１０℃まで３０分間加熱することによって、２−｛［（５−シアノピリジン−３−イル）アミノ］スルホニル｝安息香メチルを用いて式（Ｉ）の化合物を調製した。この溶液を室温まで冷まして置いて、溶媒を蒸発させた。粗製生成物をＳｉＯ_２カラムクロマトグラフィーによって精製した。

Mixture of methyl 2-{[(5-cyanopyridin-3-yl) amino] sulfonyl} benzoate (1 eq) and the appropriate amine (1.5 eq) dissolved in CH ₃ CN (0.35 M) And the compound of formula (I) is prepared with 2-{[(5-cyanopyridin-3-yl) amino] sulfonyl} benzoic acid methyl by heating to about 110 ° C. in microwave for 30 minutes did. The solution was allowed to cool to room temperature and the solvent was evaporated. The crude product was purified by SiO ₂ column chromatography.

(Example F)
Synthesis of N- (1,1-dimethyl-2-morpholin-4-ylethyl) -2-[(pyridin-3-ylmethyl) sulfinyl] benzamide

ステップ１：２−メルカプト安息香酸メチル（２）：
酸１（１７０．０ｇ、１．１ｍｏｌ）、Ｈ_２ＳＯ_４（２０ｍＬ、０．３７ｍｏｌ）および無水ＭｅＯＨ（３００ｍＬ）を２日間還流させた。溶媒を減圧下で蒸発させた。水を加え、混合物をＣＨ_２Ｃｌ_２（３×１０００ｍＬ）で抽出した。有機層を混ぜ合わせ、ＮａＨＣＯ_３水溶液（２×３００ｍＬ）、水（２×２５０ｍＬ）、ブライン（５００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させて、粗製化合物２（１６５．０ｇ、８９．６％）をもたらした。これは、さらに精製しないで使用した。

Step 1: Methyl 2-mercaptobenzoate (2):
Acid 1 (170.0 g, 1.1 mol), H ₂ SO ₄ (20 mL, 0.37 mol) and anhydrous MeOH (300 mL) were refluxed for 2 days. The solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 1000 mL). The organic layers were combined and washed with aqueous NaHCO ₃ (2 × 300 mL), water (2 × 250 mL), brine (500 mL), dried over Na ₂ SO ₄ and crude compound 2 (165.0 g, 89.6). %). This was used without further purification.

Step 2: Methyl 2- (pyridin-3-ylmethylthio) benzoate (3):
A mixture of compound 2 (70.0 g, 0.4167 mol), 1- (bromomethyl) benzene (82.8 g, 0.5 mol), K ₂ CO ₃ (350 g, 2.49 mol) and CH ₃ CN (500 mL) overnight. Refluxed. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. After adding water, the mixture was extracted with CH ₂ Cl ₂ (3 × 500 mL). The organic layers were combined, washed with aqueous Na ₂ CO ₃ (2 × 200 mL), water (2 × 300 mL), brine (300 mL) and dried over Na ₂ SO ₄ . After evaporation, crude compound 3 was obtained (64.0 g, 59.4%). This was used without further purification.

Step 3: 2- (Pyridin-3-ylmethylthio) benzoic acid (4):
To a solution of compound 3 (55.0 g, 0.212 mol) in MeOH / H ₂ O (300 mL / 50 mL) was added LiOH · H ₂ O (17.8 g, 0.425 mol) little by little at 0 ° C. The reaction mixture was stirred at room temperature overnight and TLC showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with Et ₂ O (2 × 1 L) to remove neutral impurities. The aqueous layer was adjusted to pH 3-4 with 1N aqueous HCl (50 mL) and extracted with EtOAc (2 × 1 L). The combined organic phase was washed with water (2 × 200 mL), brine (300 mL), dried over Na ₂ SO ₄ and concentrated to give compound 4 (35.0 g, 67%). This was used without further purification.

Step 4: N- (2-Methyl-1-morpholinopropan-2-yl) -2- (pyridin-3-ylmethylthio) benzamide (5):
To an anhydrous DMF / DMSO solution of acid 4 (2.75 g, 11.2 mmol) and 2-methyl-1-morpholinopropan-2-amine (1.12 mL, 7.4 mmol)), EDCI (2.58 g, 13. 32 mmol), HOBt (0.182 g, 13.32 mmol) and NMM (3.35 mL, 29.6 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo. After adding water (10 mL), the mixture was extracted with CH ₂ Cl ₂ . The organic layers were combined, washed with 1N aqueous NaOH (15 mL), water (3 × 10 mL), brine (50 mL) and dried over MgSO ₄ . The solvent was removed under reduced pressure; the residue was purified by column chromatography (silica gel, EtOAc / petroleum 1: 5) to give 5 (2.0 g, 50%). ¹ H NMR (400 MHz, chloroform-D) δ ppm 8.46 (d, 1H) 8.43 (dd, 1H) 7.52 to 7.56 (m, 1H) 7.45 to 7.50 (m, 1H) 7.20-7.24 (m, 2H) 7.13-7.19 (m, 1H) 6.66 (s, 1H) 4.08 (s, 2H) 3.63 (t, 4H) 2.57 to 2.62 (m, 6H) 1.44 (s, 6H)

Step 5: N- (2-Methyl-1-morpholinopropan-2-yl) -2- (pyridin-3-ylmethylsulfinyl) benzamide (6):
To a solution of intermediate 5 (0.143, 0.370 mmol) in CHCl ₃ (6 ml) was added Et ₄ NBr (0.004 g, 0.018 mmol) and IBX (0.142 g, 0.507 mmol) and the reaction mixture was Stir at room temperature for 1 hour. The mixture was diluted with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (0-5% MeOH / CH ₂ Cl ₂ ) to give compound 17 (0.026 g, 18%). ¹ H NMR (400 MHz, chloroform-D) d ppm 8.45 (d, 1H) 8.07 to 8.11 (m, 1H) 7.39 to 7.53 (m, 5H) 7.13 to 7. 20 (m, 1H) 7.05 (s, 1H) 4.40 (d, 1H) 4.19 (d, 1H) 3.61 to 3.70 (m, 4H) 2.48 to 2.65 ( m, 6H) 1.46 (d, 6H)

(Example G)
General Method for BOC Deprotection To a suitable BOC protected amine (1 eq) in MeOH (0.1 M), Dowex 50WX2-400 ion exchange resin (10 eq) is added and the mixture is heated to 40 ° C. For 3 hours. The mixture is then allowed to cool to room temperature and filtered. The resin was washed with 3 portions of MeOH. The product is then released from the resin by treatment with a solution of 20% NH ₄ OH / MeOH added in 3 portions. The basic alcohol wash is concentrated in vacuo to produce the desired deprotected amine.

(Example 42)
N- (3-methylbutyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide

２−［（ピリジン−３−イルアミノ）スルホニル］安息香酸メチルおよび３−メチルブチルアミンを用いて、上記手順に従って表題化合物を調製した。２．０ｇを酢酸エチル（２０ｍＬ）中に溶解させ、加熱還流することによって、表題化合物をさらに精製した。化合物が完全に溶解してから、得られた溶液を室温まで非常にゆっくり冷ました。得られた結晶を室温で３０分静置し、その時間後それらを漏斗を用いてろ過し、冷酢酸エチル（２０ｍＬ）で洗浄し、高真空下で１６時間乾燥させて、表題化合物を白色結晶性固体（１．６７ｇ、８４％）としてもたらした。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ８．６４（ｓ，１Ｈ）８．２６〜８．４３（ｍ，２Ｈ）７．６０〜７．６８（ｍ，２Ｈ）７．４５〜７．５９（ｍ，２Ｈ）７．３９（ｔ，１Ｈ）７．１２〜７．２１（ｍ，１Ｈ）６．０８〜６．１７（ｍ，１Ｈ）３．５２（ｑ，２Ｈ）１．６７〜１．７９（ｍ，１Ｈ）１．５７（ｑ，２Ｈ）０．９８（ｄ，６Ｈ）。

The title compound was prepared following the above procedure using methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate and 3-methylbutylamine. The title compound was further purified by dissolving 2.0 g in ethyl acetate (20 mL) and heating to reflux. After the compound was completely dissolved, the resulting solution was cooled very slowly to room temperature. The crystals obtained are left at room temperature for 30 minutes, after which time they are filtered using a funnel, washed with cold ethyl acetate (20 mL) and dried under high vacuum for 16 hours to give the title compound as white crystals. As a solid (1.67 g, 84%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (s, 1H) 8.26-8.43 (m, 2H) 7.60-7.68 (m, 2H) 7.45-7.59 (m , 2H) 7.39 (t, 1H) 7.12 to 7.21 (m, 1H) 6.08 to 6.17 (m, 1H) 3.52 (q, 2H) 1.67 to 1.79 (M, 1H) 1.57 (q, 2H) 0.98 (d, 6H).

(Example 43)
N- (3-fluorobenzyl) -2-[(pyridin-3-ylamino) sulfonyl] benzamide

２−［（ピリジン−３−イルアミノ）スルホニル］安息香酸メチルおよび３−フルオロベンジルアミンを用いて、上記手順に従って表題化合物を調製した。２５ｇをＥｔＯＨ（３００ｍＬ）中に溶解させ、水浴を用いて８０℃まで穏やかに加熱することによって、表題化合物をさらに精製した。次いで得られた固体物質をゆっくり溶解させ、ＥｔＯＨ（５０ｍＬ）をさらに加えて、全ての固体を完全に溶解させた。この溶液を室温で放置して、１時間結晶化させた。得られた結晶を捕集し、高真空下で１６時間乾燥させて、表題化合物を結晶性固体（２１ｇ、８４％）としてもたらした。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ９．７６（ｓ，１Ｈ）９．３２（ｔ，１Ｈ）８．３１（ｄ，１Ｈ）８．２５（ｄ，１Ｈ）７．６６〜７．７８（ｍ，２Ｈ）７．５０〜７．６５（ｍ，３Ｈ）７．３９（ｑ，１Ｈ）７．２３〜７．２９（ｍ，３Ｈ）７．０９（ｔ，１Ｈ）４．５４（ｄ，２Ｈ）。

The title compound was prepared according to the above procedure using methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate and 3-fluorobenzylamine. The title compound was further purified by dissolving 25 g in EtOH (300 mL) and gently heating to 80 ° C. using a water bath. The resulting solid material was then slowly dissolved and more EtOH (50 mL) was added to completely dissolve all solids. The solution was left to stand at room temperature for crystallization for 1 hour. The resulting crystals were collected and dried under high vacuum for 16 hours to yield the title compound as a crystalline solid (21 g, 84%). ¹ H NMR (400 MHz, DMSO-D6) δ 9.76 (s, 1H) 9.32 (t, 1H) 8.31 (d, 1H) 8.25 (d, 1H) 7.66-7.78 ( m, 2H) 7.50-7.65 (m, 3H) 7.39 (q, 1H) 7.23-7.29 (m, 3H) 7.09 (t, 1H) 4.54 (d, 2H).

(Example 63)
N-butyl-2-[(pyridin-3-ylamino) sulfonyl] benzamide

２−［（ピリジン−３−イルアミノ）スルホニル］安息香酸メチルおよびｎ−ブチルアミンを用いて、上記手順に従って表題化合物を調製した。２．０ｇを酢酸エチル（１０ｍＬ）中に溶解させることによって、表題化合物をさらに精製した。次いで濁るまでこの溶液にヘキサンを１滴ずつ加えた。次いで酢酸エチルを数滴加えて、透明な溶液を得た。得られた溶液を室温で約４８時間放置した。得られた固体を捕集し、２０％酢酸エチル／ヘキサン（３×１５０ｍＬ）で洗浄し、高真空下において終夜室温で乾燥させて、表題化合物を結晶性固体（１．６４ｇ、８２％）としてもたらした。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−Ｄ６）δ９．９０〜１０．００（ｍ，１Ｈ）８．７３（ｔ，１Ｈ）８．２８〜８．３７（ｍ，２Ｈ）７．７１〜７．７６（ｍ，１Ｈ）７．６１〜７．７０（ｍ，２Ｈ）７．４９〜７．５７（ｍ，２Ｈ）７．３５〜７．４４（ｍ，１Ｈ）３．２５（ｑ，２Ｈ）１．５１〜１．５４（ｍ，２Ｈ）１．２９〜１．４０（ｍ，２Ｈ）０．９０（ｔ，３Ｈ）。

The title compound was prepared according to the above procedure using methyl 2-[(pyridin-3-ylamino) sulfonyl] benzoate and n-butylamine. The title compound was further purified by dissolving 2.0 g in ethyl acetate (10 mL). Hexane was then added dropwise to the solution until cloudy. A few drops of ethyl acetate were then added to give a clear solution. The resulting solution was left at room temperature for about 48 hours. The resulting solid was collected, washed with 20% ethyl acetate / hexane (3 × 150 mL) and dried under high vacuum overnight at room temperature to give the title compound as a crystalline solid (1.64 g, 82%). Brought. ¹ H NMR (400 MHz, DMSO-D6) δ 9.90 to 10.00 (m, 1H) 8.73 (t, 1H) 8.28 to 8.37 (m, 2H) 7.71 to 7.76 ( m, 1H) 7.61-7.70 (m, 2H) 7.49-7.57 (m, 2H) 7.35-7.44 (m, 1H) 3.25 (q, 2H) 51-1.54 (m, 2H) 1.29-1.40 (m, 2H) 0.90 (t, 3H).

(Examples 1 to 393)
The following examples were prepared according to Example 2 using the appropriate compounds of Formulas 3 and 4 (as described in Schemes 1 and 2). The compound of formula 3 was prepared as described above, and the compound of formula 4 was either commercially available or prepared using methods known to those skilled in the art.

(Example G)
In vitro activity data for the examples The determination of _{K iapp} of the compounds of the present invention for determining the recombinant CYP3A4 enzyme compound _{K iapp,} was performed as follows. After the addition of substrate and inhibitor, the assay was performed in 100 mM sodium phosphate buffer pH 7.0 containing 5 mM TCEP and 2% dimethylformamide (final concentration). A typical reaction to determine the K _iapp value was performed in a solid black Costar u-bottom 96-well polypropylene plate at room temperature. In each well, recombinant CYP3A4 enzyme (5.5 nM or 8 nM, final concentration depends on the commercial source of the enzyme) was pre-incubated in assay buffer for at least 30 minutes in the presence of inhibitors. When pre-incubation is complete (approximately 30 minutes), the reaction is initiated by adding NADPH (200 uM, final concentration), and 7-benzyloxy-4- (trifluoromethyl) -coumarin (BFC) (5 uM, final concentration). did. The oxidation of the coumarin substrate was recorded by a 96 well plate reader POLARstar (BMG LABTECH, Offenburg, Germany).

The initial reaction rate was measured during the first 5 minutes of the reaction, in which the release of the fluorescent product was linear with time in the absence and presence of various concentrations of inhibitor. For non-partial & partial inhibitors, the K _iapp values are Morrison, JF (Morrison JF. Biochim Biophys Acta. 1969, 185: 269-86) and Szelasseck SE et al. V., Serban, M., and Vlad, M.O.Biochem.J. 1988, 254: 311-312) determined by using the equation for a strong-binding inhibitor did.

  The fluorescent substrate BFC was purchased from Sigma (St Louis, MO, USA). Two commercial sources of recombinant enzyme were used in this study: recombinant CYP3A4-b5 enzyme (Baculosomes®) was purchased from Invitrogen (Carlsbad, Calif., USA) and recombinant CYP3A4 + b5 enzyme (Supersomes ( (Registered trademark)) was purchased from BD Biosciences (Woburn, Massachusetts, USA).

2. Determination of IC ₅₀ for CYP3A4 by measuring inhibition of testosterone metabolism The assay was performed using a standard 96 well plate design. IC50 values are calculated from the percent inhibition determined for each test compound at six concentrations (eg: 750, 250, 83.3, 27.8, 9.3 and 3.1 nM). The incubation substrate mix contains 25 μM testosterone, 0.1 mg / mL human liver microsomes, 1 mM NADPH, and potassium phosphate buffer (100 mM, pH 7.4). Quantification of the metabolite peak area ratio relative to the internal standard is determined by LC-MS / MS analysis. The production of 6-β-OH-testosterone from testosterone metabolism is confirmed by comparison with a standard curve generated for the metabolite 8 minutes after incubation.

  Samples were from a Sciex API Masspipe, USA, USA, USA, USA, USA, USA, USA, USA, USA, USA In MRM mode. Phenomenex Synergi, 4μ, Polar-RP, 10 × 2.0 mm column (Phenomenex, USA) for separation using mobile phase composition of 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). Torrance, CA) was used. The following gradient was used:

  The sample injection volume was 10 μL, and 0.4 mL / min after the column was sent to the mass spectrometer to divide the flow rate. Analysis was performed using the following API 3000 mass spectrometer settings:

3. Determination of IC ₅₀ for CYP3A4 by measuring inhibition of midazolam metabolism The assay was performed using a standard 96 well plate design. IC50 is calculated from the percent inhibition determined for each test compound at six concentrations (eg: 750, 250, 83.3, 27.8, 9.3 and 3.1 nM). The incubation substrate mix contains 2 μM midazolam, 0.1 mg / mL human liver microsomes, 1 mM NADPH, and potassium phosphate buffer (100 mM, pH 7.4). Quantification of the metabolite peak area ratio relative to the internal standard is determined by LC-MS / MS analysis. The production of 1-hydroxymidazolam from midazolam metabolism is confirmed by comparison with a standard curve generated for the metabolite 8 minutes after incubation.

  Samples were from a Sciex API Masspipe, USA, USA, USA, USA, USA, USA, USA, USA, USA, USA In MRM mode. Phenomenex Synergi, 4μ, Polar-RP, 10 × 2.0 mm column (Phenomenex, USA) for separation using mobile phase composition of 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). Torrance, CA) was used. The following gradient was used:

  The sample injection volume was 10 μL, and 0.4 mL / min after the column was sent to the mass spectrometer to divide the flow rate. Analysis was performed using the following API 3000 mass spectrometer settings:

Claims (22)

Compound of formula (I)

(Where
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen, —CN, OR ^12a , N (R ^12a R ^12b ) and —CF ₃ ;
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ , R ⁸ , and R ⁹ are hydrogen;
R ⁷ is selected from hydrogen, halogen, —OR ^12a , —O (CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl and —O (CR ^12a R ^12b ) _t N (R ^12a R ^12b ),
R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl, and R ¹¹ is — (CR ^12a R ^12b ) _t C ₁ -C ₆ alkyl, — (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl, _{^{- (CR 12a R 12b) t}} C 6 ~C 10 _{^{aryl, - (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, and ^- is selected from ^{(CR 12a R} _{12b) t} heteroaryl, wherein _C 1 -C Each of the ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ aryl, C ₂ -C ₁₀ heterocyclyl, heteroaryl groups may be substituted with one or more R ¹³ , or R ¹⁰ and ^{R 11,} together with the atom to which they are attached, one or more _C 2 may be substituted by ^{R 13} _{-C 10} Heteroshiku Form a group,
Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ^12a and R ^12b , together with the atoms to which they are attached, C ₃ -C ₁₁ cycloalkyl or C ₂ to form a -C ₁₀ heterocyclyl group,
Each R ¹³ is independently C ₁ -C ₆ alkyl, halogen,-(CR ^12a R ^12b ) _t CN,-(CR ^12a R ^12b ) _t CF ₃ ,-(CR ^12a R ^12b ) _t OCF ₃ ,- (CR ^12a R ^12b ) _t C ₃ -C ₁₁ cycloalkyl,-(CR ^12a R ^12b ) _t C ₆ -C ₁₀ aryl,-(CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl,-(CR ^12a R ^12b) _{t ^{heteroaryl, -O (CR 12a R 12b)}} t R 12a, -O (CR 12a R 12b) t C 6 ~C 10 _{^{aryl, -O (CR 12a R 12b)}} t C 2 ~C 10 heterocyclyl, -O ^{(CR 12a R} _{12b) t ^{heteroaryl, - (CR 12a R 12b)}} t CO 2 (C 1 ~C 6 alkyl), _{^{- (CR 12a R 12b) t}} N (R 12a R 12b), - (CR 12a R 12b) t C (O) NR 12a R 12b, - (CR 12a R 12b) t OR 12a, - (CR 12a R 12b ) _T S (O) R ^12a , and — (CR ^12a R ^12b ) _t S (O) ₂ R ^12a , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₁ cycloalkyl, C ₆ -C ₁₀ The aryl, C ₂ -C ₁₀ heterocyclyl, and heteroaryl groups may each be substituted with one or more R ¹⁴ ,
Each R ¹⁴ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OR ^12a ;
Each t is independently selected from 0, 1, 2, 3, 4, 5, and 6), or a pharmaceutically acceptable salt or solvate thereof. ^2. The compound according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen, —CN, —OR ^12a and —CF _3. A pharmaceutically acceptable salt or solvate thereof. The compound according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. R ⁷ is selected from hydrogen, halogen, —OR ^12a , —O (CR ^12a R ^12b ) _t C ₂ -C ₁₀ heterocyclyl and —O (CR ^12a R ^12b ) _t N (R ^12a R ^12b ), wherein said heterocyclyl 4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein is piperazine, piperidine or morpholine. The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ is hydrogen. R ¹¹ is — (CH ₂ ) C ₆ -C ₁₀ aryl or — (CH ₂ ) ₂ C ₆ -C ₁₀ aryl, and said C ₆ -C ₁₀ aryl is substituted with one or more R ¹³ May have been
R ^12a is hydrogen or C ₁ -C ₆ alkyl;
Each ^{R 13} is, independently _C 1 -C ₆ alkyl, halogen, -CN, -CF _3, and is selected from -OCF _3, A compound according to claim 5, or a pharmaceutically acceptable salt or solvate Japanese products. R ¹ , R ³ , and R ⁴ are hydrogen,
R ² _is, C 1 -C ₆ alkyl, halogen, ^-CN, an ^{-OR 12a} or -CF _3,, the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 6. R ² is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ¹⁰ is hydrogen or —CH ₃ ,
The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, -Cl, -F, -CN, -CF ₃ , and -OCF _3. Possible salt or solvate. R ¹ , R ² , and R ⁴ are hydrogen,
R ³ is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
R ¹⁰ is hydrogen or —CH ₃ ,
The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, -Cl, -F, -CN, -CF ₃ , and -OCF _3. Possible salt or solvate. R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen, —CN, —OR ^12a , and —CF ₃ ;
R ⁵ is hydrogen;
R ⁷ is hydrogen or halogen;
The compound according to claim 1, wherein R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₂ -C ₁₀ heterocyclyl group optionally substituted by one or more R ^13. A pharmaceutically acceptable salt or solvate thereof. R ⁷ is hydrogen, a compound or a pharmaceutically acceptable salt or solvate thereof according to claim 10. R ^12a is hydrogen or C ₁ -C ₆ alkyl;
The compound according to claim 11 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, —CN, —CF ₃ , and —OCF _3. Japanese products. R ¹ , R ³ , and R ⁴ are hydrogen,
R ² _is, C 1 -C ₆ alkyl, halogen, ^-CN, an ^{-OR 12a} or -CF _3,, the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 12. R ² is C ₁ -C ₆ alkyl, —Cl, —F, —CN, —OCH ₃ , —OCH ₂ CH ₃ , or —CF ₃ ;
Each ^{R 13} is, independently _C 1 -C ₆ alkyl, halogen, -CN, -CF _3, and is selected from -OCF _3, A compound according to claim 13 or a pharmaceutically acceptable salt or solvate Japanese products. R ¹ , R ² , and R ⁴ are hydrogen,
R ³ _is, C 1 -C _{6 alkyl, -Cl, -F, -CN, -OCH} 3, -OCH 2 CH 3, or -CF _3, A compound according to claim 12 or a pharmaceutically acceptable Possible salt or solvate. N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide;
N- (3,4-difluorobenzyl) -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide;
N- [2- (2-fluorophenyl) ethyl] -2-{[(5-methoxypyridin-3-yl) amino] sulfonyl} benzamide;
N- [4-fluoro-3- (trifluoromethyl) benzyl] -2-{[(4-methoxypyridin-3-yl) amino] sulfonyl} benzamide;
N- (3,4-difluorobenzyl) -2-{[(4-ethoxypyridin-3-yl) amino] sulfonyl} benzamide; and N- (3,4-difluorobenzyl) -2-{[(4- A compound selected from the group consisting of ethoxypyridin-3-yl) amino] sulfonyl} -N-methylbenzamide, or a pharmaceutically acceptable salt or solvate thereof.   17. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 16, and a pharmaceutically acceptable carrier. An effective amount of (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3.2.1] octane -8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide),
1-endo- {8-[(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carboxylate, or N-{(1S) -3- [3-endo- (5-isobutyryl-2) -Methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- ( The pharmaceutical composition according to claim 17, further comprising (3-fluorophenyl) propyl} acetamide). Amprenavir, Nelfinavir, Ritonavir, Saquinavir, Inbilase, Lopinavir,
Atazanavir, Parinaville, Indinaville, Chipranavir, Darunaville, Brecanaville,
(4R) -N-allyl-3-{(2S, 3S) -2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl- 18. The pharmaceutical composition of claim 17, further comprising an HIV protease inhibitor selected from 1,3-thiazolidine-4-carboxamide, and phosamprenavir calcium.   Use of a first compound and a second compound in the preparation of a medicament for treating an HIV infection in an HIV-infected mammal, wherein the first compound is any one of claims 1-16. Use wherein the second compound is an anti-HIV compound.   The second compound is (N-{(1S) -3- [3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl] -exo-8-azabicyclo [3.2. 1] Oct-8-yl} -1-phenylpropyl) -4,4-difluorocyclohexanecarboxamide), 1-endo- {8-[(3S) -3- (acetylamino) -3- (3-fluorophenyl) ) Propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carvone Ethyl acetate or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-1 -Yl) -8-azabicyclo [3 2.1] oct-8-yl] is 1- (3-fluorophenyl) propyl} acetamide), Use according to claim 20. The second compound is amprenavir, nelfinavir, ritonavir, saquinavir, inbilase, lopinavir, atazanavir, parinavir, indinavir, tipranavir, darunavir, branavir, (4R) -N-allyl-3-{(2S, 3S) 2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4-phenylbutanoyl} -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, and phosamprenavir calcium 21. Use according to claim 20 , selected from: